1. |
Cofas Vargas L. F., Olivos-Ramirez G. E., Chwastyk M.♦, Moreira R.A.♦, Baker J. L.♦, Marrink S. J.♦, Poma Bernaola A.M., Nanomechanical footprint of SARS-CoV-2 variants in complex with a potent nanobody by molecular simulations,
NANOSCALE, ISSN: 2040-3364, DOI: 10.1039/D4NR02074J, Vol.16, No.40, pp.18824-18834, 2024Abstract: Rational design of novel antibody therapeutics against viral infections such as coronavirus relies on surface complementarity and high affinity for their effectiveness. Here, we explore an additional property of protein complexes, the intrinsic mechanical stability, in SARS-CoV-2 variants when complexed with a potent antibody. In this study, we utilized a recent implementation of the GōMartini 3 approach to investigate large conformational changes in protein complexes with a focus on the mechanostability of the receptor-binding domain (RBD) from WT, Alpha, Delta, and XBB.1.5 variants in complex with the H11-H4 nanobody. The analysis revealed moderate differences in mechanical stability among these variants. Also, we identified crucial residues in both the RBD and certain protein segments in the nanobody that contribute to this property. By performing pulling simulations and monitoring the presence of specific native and non-native contacts across the protein complex interface, we provided mechanistic insights into the dissociation process. Force-displacement profiles indicate a tensile force clamp mechanism associated with the type of protein complex. Our computational approach not only highlights the key mechanostable interactions that are necessary to maintain overall stability, but it also paves the way for the rational design of potent antibodies that are mechanostable and effective against emergent SARS-CoV-2 variants. Keywords: SARS-CoV-2, GōMartini 3, Nanomechanics, Protein complexes, protein engineering, MD, native contacts Affiliations:
Cofas Vargas L. F. | - | IPPT PAN | Olivos-Ramirez G. E. | - | IPPT PAN | Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Moreira R.A. | - | other affiliation | Baker J. L. | - | The College of New Jersey (US) | Marrink S. J. | - | other affiliation | Poma Bernaola A.M. | - | IPPT PAN |
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2. |
Cofas Vargas L.F., Azevedo Rodrigo M.♦, Poblete S.♦, Chwastyk M.♦, Poma Bernaola A.M.♦, The GōMartini Approach: Revisiting the Concept of Contact Maps and the Modelling of Protein Complexes,
ACTA PHYSICA POLONICA A, ISSN: 0587-4246, DOI: 10.12693/APhysPolA.145.S9, Vol.145, No.3, pp.S9-S20, 2024Abstract: We present a review of a series of contact maps for the determination of native interactions in proteins and nucleic acids based on a distance threshold. Such contact maps are mostly based on physical and chemical construction, and yet they are sensitive to some parameters (e.g., distances or atomic radii) and can neglect some key interactions. Furthermore, we also comment on a new class of contact maps that only requires geometric arguments. The contact map is a necessary ingredient to build a robust Gō-Martini model for proteins and their complexes in the Martini 3 force field. We present the extension of a popular structure-based Gō--like approach to the study of protein–sugar complexes, and the limitations of this approach are also discussed. The Gō-Martini approach was first introduced by Poma et al. (J. Chem. Theory Comput. 13, 1366 (2017)) in Martini 2 force field, and recently, it has gained the status of gold standard for protein simulation undergoing conformational changes in Martini 3 force field. We discuss several studies that have provided support for this approach in the context of the biophysical community. Keywords: Martini 3,Structure-based coarse-graining,SMFS,biomolecules,GoMartini Affiliations:
Cofas Vargas L.F. | - | IPPT PAN | Azevedo Rodrigo M. | - | other affiliation | Poblete S. | - | other affiliation | Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Poma Bernaola A.M. | - | other affiliation |
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3. |
Ray A.♦, Thu Thi Minh T.♦, Santos Natividade Rita d.♦, Azevedo Rodrigo M.♦, Joshua S.♦, Danahe M.♦, Koehler M.♦, Simon P.♦, Qingrong Z.♦, Fabrice B.♦, Laurent G.♦, Poma Bernaola A.M., Alsteens D.♦, Single-Molecule Investigation of the Binding Interface Stability of SARS-CoV-2 Variants with ACE2,
ACS Nanoscience Au, ISSN: 2694-2496, DOI: 10.1021/acsnanoscienceau.3c00060, pp.1-10, 2024Abstract: The SARS-CoV-2 pandemic spurred numerous research endeavors to comprehend the virus and mitigate its global severity. Understanding the binding interface between the virus and human receptors is pivotal to these efforts and paramount to curbing infection and transmission. Here we employ atomic force microscopy and steered molecular dynamics simulation to explore SARS-CoV-2 receptor binding domain (RBD) variants and angiotensin-converting enzyme 2 (ACE2), examining the impact of mutations at key residues upon binding affinity. Our results show that the Omicron and Delta variants possess strengthened binding affinity in comparison to the Mu variant. Further, using sera from individuals either vaccinated or with acquired immunity following Delta strain infection, we assess the impact of immunity upon variant RBD/ACE2 complex formation. Single-molecule force spectroscopy analysis suggests that vaccination before infection may provide stronger protection across variants. These results underscore the need to monitor antigenic changes in order to continue developing innovative and effective SARS-CoV-2 abrogation strategies. Keywords: SARS-Cov-2,Molecular Dynamics ,Immunity,SMFS,Nanomechanics,Free Energy,Jarzynski,Receptor,Protein complex,interfaces Affiliations:
Ray A. | - | other affiliation | Thu Thi Minh T. | - | other affiliation | Santos Natividade Rita d. | - | other affiliation | Azevedo Rodrigo M. | - | other affiliation | Joshua S. | - | other affiliation | Danahe M. | - | other affiliation | Koehler M. | - | other affiliation | Simon P. | - | other affiliation | Qingrong Z. | - | other affiliation | Fabrice B. | - | other affiliation | Laurent G. | - | other affiliation | Poma Bernaola A.M. | - | IPPT PAN | Alsteens D. | - | other affiliation |
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4. |
Poblete S.♦, Pantano S.♦, Okazaki K.♦, Liang Z.♦, Kremer K.♦, Poma Adolfo B., Editorial: Recent advances in computational modelling of biomolecular complexes,
Frontiers in Chemistry, ISSN: 2296-2646, DOI: 10.3389/fchem.2023.1200409, Vol.11, pp.1200409-1-3, 2023, EDITORIALKeywords: coarse-grained method, machine learning, multiscale approach, biopolymers, aggregation, GōMartini approach, Martini 3, nanomechanics Affiliations:
Poblete S. | - | other affiliation | Pantano S. | - | other affiliation | Okazaki K. | - | other affiliation | Liang Z. | - | other affiliation | Kremer K. | - | other affiliation | Poma Adolfo B. | - | IPPT PAN |
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5. |
Liu Z.♦, Moreira R.A., Dujmović A.♦, Liu H.♦, Yang B.♦, Poma A.B., Nash M.A.♦, Mapping mechanostable pulling geometries of a therapeutic anticalin/CTLA-4 protein complex,
Nano Letters, ISSN: 1530-6984, DOI: 10.1021/acs.nanolett.1c03584, Vol.22, pp.179-187, 2022Abstract: We used single-molecule AFM force spectroscopy (AFM-SMFS) in combination with click chemistry to mechanically dissociate anticalin, a non-antibody protein binding scaffold, from its target (CTLA-4), by pulling from eight different anchor residues. We found that pulling on the anticalin from residue 60 or 87 resulted in significantly higher rupture forces and a decrease in koff by 2–3 orders of magnitude over a force range of 50–200 pN. Five of the six internal anchor points gave rise to complexes significantly more stable than N- or C-terminal anchor points, rupturing at up to 250 pN at loading rates of 0.1–10 nN s^–1. Anisotropic network modeling and molecular dynamics simulations helped to explain the geometric dependency of mechanostability. These results demonstrate that optimization of attachment residue position on therapeutic binding scaffolds can provide large improvements in binding strength, allowing for mechanical affinity maturation under shear stress without mutation of binding interface residues. Keywords: atomic force microscopy, protein engineering, single-molecule force spectroscopy, mechanical anisotropy, click chemistry, Go̅-Martini model, PCA Affiliations:
Liu Z. | - | other affiliation | Moreira R.A. | - | IPPT PAN | Dujmović A. | - | other affiliation | Liu H. | - | Imperial College London (GB) | Yang B. | - | other affiliation | Poma A.B. | - | IPPT PAN | Nash M.A. | - | other affiliation |
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6. |
Thi Minh Thu T.♦, Moreira R.A., Weber S.A.L.♦, Poma A.B., Molecular Insight into the Self-Assembly Process of Cellulose Iβ Microfibril,
International Journal of Molecular Sciences, ISSN: 1422-0067, DOI: 10.3390/ijms23158505, Vol.23, No.15, pp.8505-1-18, 2022Abstract: The self-assembly process of β-D-glucose oligomers on the surface of cellulose Iβ microfibril involves crystallization, and this process is analyzed herein, in terms of the length and flexibility of the oligomer chain, by means of molecular dynamics (MD) simulations. The characterization of this process involves the structural relaxation of the oligomer, the recognition of the cellulose I microfibril, and the formation of several hydrogen bonds (HBs). This process is monitored on the basis of the changes in non-bonded energies and the interaction with hydrophilic and hydrophobic crystal faces. The oligomer length is considered a parameter for capturing insight into the energy landscape and its stability in the bound form with the cellulose I microfibril. We notice that the oligomer–microfibril complexes are more stable by increasing the number of hydrogen bond interactions, which is consistent with a gain in electrostatic energy. Our studies highlight the interaction with hydrophilic crystal planes on the microfibril and the acceptor role of the flexible oligomers in HB formation. In addition, we study by MD simulation the interaction between a protofibril and the cellulose I microfibril in solution. In this case, the main interaction consists of the formation of hydrogen bonds between hydrophilic faces, and those HBs involve donor groups in the protofibril. Keywords: cellulose I, self-assembly, stability, molecular dynamics, Charmm36, β-D-glucose Affiliations:
Thi Minh Thu T. | - | Lodz University of Technology (PL) | Moreira R.A. | - | IPPT PAN | Weber S.A.L. | - | Max Planck Institute for Polymer Research (DE) | Poma A.B. | - | IPPT PAN |
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7. |
Moreira R.A., Weber S.A.L.♦, Poma A.B.♦, Martini 3 model of cellulose microfibrils: on the route to capture large conformational changes of polysaccharides,
Molecules, ISSN: 1420-3049, DOI: 10.3390/molecules27030976, Vol.27, No.3, pp.976-1-11, 2022Abstract: High resolution data from all-atom molecular simulations is used to parameterize a Martini 3 coarse-grained (CG) model of cellulose I allomorphs and cellulose type-II fibrils. In this case, elementary molecules are represented by four effective beads centred in the positions of O2, O3, C6, and O6 atoms in the D-glucose cellulose subunit. Non-bonded interactions between CG beads are tuned according to a low statistical criterion of structural deviation using the Martini 3 type of interactions and are capable of being indistinguishable for all studied cases. To maintain the crystalline structure of each single cellulose chain in the microfibrils, elastic potentials are employed to retain the ribbon-like structure in each chain. We find that our model is capable of describing different fibril-twist angles associated with each type of cellulose fibril in close agreement with atomistic simulation. Furthermore, our CG model poses a very small deviation from the native-like structure, making it appropriate to capture large conformational changes such as those that occur during the self-assembly process. We expect to provide a computational model suitable for several new applications such as cellulose self-assembly in different aqueous solutions and the thermal treatment of fibrils of great importance in bioindustrial applications. Keywords: cellulose I allomorphs, cellulose II, Martini 3, large conformational changes, twist, molecular dynamics, coarse-grained model, aggregation Affiliations:
Moreira R.A. | - | IPPT PAN | Weber S.A.L. | - | Max Planck Institute for Polymer Research (DE) | Poma A.B. | - | other affiliation |
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8. |
Koehler M.♦, Ray A.♦, Moreira R.A., Juniku B.♦, Poma A.B.♦, Alsteens D.♦, Molecular insights into receptor binding energetics and neutralization of SARS-CoV-2 variants,
Nature Communications, ISSN: 2041-1723, DOI: 10.1038/s41467-021-27325-1, Vol.12, pp.6977-1-13, 2021Abstract: Despite an unprecedented global gain in knowledge since the emergence of SARS-CoV-2, almost all mechanistic knowledge related to the molecular and cellular details of viral replication, pathology and virulence has been generated using early prototypic isolates of SARS-CoV-2. Here, using atomic force microscopy and molecular dynamics, we investigated how these mutations quantitatively affected the kinetic, thermodynamic and structural properties of RBD—ACE2 complex formation. We observed for several variants of concern a significant increase in the RBD—ACE2 complex stability. While the N501Y and E484Q mutations are particularly important for the greater stability, the N501Y mutation is unlikely to significantly affect antibody neutralization. This work provides unprecedented atomistic detail on the binding of SARS-CoV-2 variants and provides insight into the impact of viral mutations on infection-induced immunity. Keywords: nanomechanics, stability, spike protein, antibody neutralization Affiliations:
Koehler M. | - | other affiliation | Ray A. | - | other affiliation | Moreira R.A. | - | IPPT PAN | Juniku B. | - | other affiliation | Poma A.B. | - | other affiliation | Alsteens D. | - | other affiliation |
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9. |
Boopathi S.♦, Poma A.B., Garduño-Juárez R.♦, An overview of several inhibitors for Alzheimer’s disease: characterization and failure,
International Journal of Molecular Sciences, ISSN: 1422-0067, DOI: 10.3390/ijms221910798, Vol.22, No.19, pp.10798-1-31, 2021Abstract: Amyloid beta (Aβ) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer’s disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aβ peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aβ experiments, as it allows to explore the binding mechanism between metal ions and Aβ oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aβ peptides. Aβ oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aβ binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aβ. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aβ dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation. Keywords: Alzheimer’s disease, amyloid β peptide, plaque formation, small molecules, M30, gabapentin, MD simulation Affiliations:
Boopathi S. | - | other affiliation | Poma A.B. | - | IPPT PAN | Garduño-Juárez R. | - | other affiliation |
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10. |
Poma A.B., Tran T.M.T.♦, Lam T.M.T.♦, Hoang N.L.♦, Mai L.S.♦, Nanomechanical stability of Aβ tetramers and fibril-like structures: molecular dynamics simulations,
JOURNAL OF PHYSICAL CHEMISTRY B, ISSN: 1520-6106, DOI: 10.1021/acs.jpcb.1c02322, Vol.125, No.28, pp.7628-7637, 2021Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder and one of the main causes of dementia. The disease is associated with amyloid beta (Aβ) peptide aggregation forming initial clusters and then fibril structure and plaques. Other neurodegenerative diseases such as type 2 diabetes, amyotrophic lateral sclerosis, and Parkinson’s disease follow a similar mechanism. Therefore, inhibition of Aβ aggregation is considered an effective way to prevent AD. Recent experiments have provided evidence that oligomers are more toxic agents than mature fibrils, prompting researchers to investigate various factors that may influence their properties. One of these factors is nanomechanical stability, which plays an important role in the self-assembly of Aβ and possibly other proteins. This stability is also likely to be related to cell toxicity. In this work, we compare the mechanical stability of Aβ-tetramers and fibrillar structures using a structure-based coarse-grained (CG) approach and all-atom molecular dynamics simulation. Our results support the evidence for an increase in mechanical stability during the Aβ fibrillization process, which is consistent with in vitro AFM characterization of Aβ42 oligomers. Namely, using a CG model, we showed that the Young modulus of tetramers is lower than that of fibrils and, as follows from the experiment, is about 1 GPa. Hydrogen bonds are the dominant contribution to the detachment of one chain from the Aβ fibril fragment. They tend to be more organized along the pulling direction, whereas in the Aβ tetramers no preference is observed. Affiliations:
Poma A.B. | - | IPPT PAN | Tran T.M.T. | - | other affiliation | Lam T.M.T. | - | other affiliation | Hoang N.L. | - | other affiliation | Mai L.S. | - | other affiliation |
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11. |
Mahmood I.♦, Poma Bernaola A., Okazaki K.♦, Optimizing Gō-MARTINI coarse-grained model for F-BAR protein on lipid membrane,
Frontiers in Molecular Biosciences, ISSN: 2296-889X, DOI: 10.3389/fmolb.2021.619381, Vol.8, pp.619381-1-10, 2021Abstract: Coarse-grained (CG) molecular dynamics (MD) simulations allow us to access much larger length and time scales than atomistic MD simulations, providing an attractive alternative to the conventional simulations. Based on the well-known MARTINI CG force field, the recently developed Gō-MARTINI model for proteins describes large-amplitude structural dynamics, which has not been possible with the commonly used elastic network model. Using the Gō-MARTINI model, we conduct MD simulations of the F-BAR Pacsin1 protein on lipid membrane. We observe that structural changes of the non-globular protein are largely dependent on the definition of the native contacts in the Gō model. To address this issue, we introduced a simple cutoff scheme and tuned the cutoff distance of the native contacts and the interaction strength of the Lennard-Jones potentials in the Gō-MARTINI model. With the optimized Gō-MARTINI model, we show that it reproduces structural fluctuations of the Pacsin1 dimer from atomistic simulations. We also show that two Pacsin1 dimers properly assemble through lateral interaction on the lipid membrane. Our work presents a first step towards describing membrane remodeling processes in the Gō-MARTINI CG framework by simulating a crucial step of protein assembly on the membrane. Keywords: Gō-MARTINI, protein complex, Pacsin, membrane remodeling, molecular dynamics, principal component analysis, RMSIP, assembly, protein contacts Affiliations:
Mahmood I. | - | other affiliation | Poma Bernaola A. | - | IPPT PAN | Okazaki K. | - | other affiliation |
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12. |
Moreira R., Vargas Guzman H.♦, Boopathi S.♦, Baker J.L.♦, Poma Bernaola A., Characterization of structural and energetic differences between conformations of the SARS-CoV-2 spike protein,
Materials, ISSN: 1996-1944, DOI: 10.3390/ma13235362, Vol.13, No.23, pp.5362-1-14, 2020Abstract: The novel coronavirus disease 2019 (COVID-19) pandemic has disrupted modern societies and their economies. The resurgence in COVID-19 cases as part of the second wave is observed across Europe and the Americas. The scientific response has enabled a complete structural characterization of the Severe Acute Respiratory Syndrome—novel Coronavirus 2 (SARS-CoV-2). Among the most relevant proteins required by the novel coronavirus to facilitate the cell entry mechanism is the spike protein. This protein possesses a receptor-binding domain (RBD) that binds the cellular angiotensin-converting enzyme 2 (ACE2) and then triggers the fusion of viral and host cell membranes. In this regard, a comprehensive characterization of the structural stability of the spike protein is a crucial step to find new therapeutics to interrupt the process of recognition. On the other hand, it has been suggested that the participation of more than one RBD is a possible mechanism to enhance cell entry. Here, we discuss the protein structural stability based on the computational determination of the dynamic contact map and the energetic difference of the spike protein conformations via the mapping of the hydration free energy by the Poisson–Boltzmann method. We expect our result to foster the discussion of the number of RBD involved during recognition and the repurposing of new drugs to disable the recognition by discovering new hotspots for drug targets apart from the flexible loop in the RBD that binds the ACE2. Keywords: COVID-19, SARS-CoV-2, spike protein, RBD, structural stability, large conformational changes, protein complexes, free energy, molecular dynamics, dynamics contact analysis Affiliations:
Moreira R. | - | IPPT PAN | Vargas Guzman H. | - | Max-Planck-Institute for Polymer Research (DE) | Boopathi S. | - | other affiliation | Baker J.L. | - | The College of New Jersey (US) | Poma Bernaola A. | - | IPPT PAN |
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13. |
Moreira R., Chwastyk M.♦, Baker J.L.♦, Vargas Guzman H.A.♦, Poma A., Quantitative determination of mechanical stability in the novel coronavirus spike protein,
NANOSCALE, ISSN: 2040-3364, DOI: 10.1039/D0NR03969A, Vol.12, No.31, pp.16409-16413, 2020Abstract: We report on the novel observation about the gain in mechanical stability of the SARS-CoV-2 (CoV2) spike (S) protein in comparison with SARS-CoV from 2002 (CoV1). Our findings have several biological implications in the subfamily of coronaviruses, as they suggest that the receptor binding domain (RBD) (~200 amino acids) plays a fundamental role as a damping element of the massive viral particle's motion prior to cell-recognition, while also facilitating viral attachment, fusion and entry. The mechanical stability via pulling of the RBD is 250 pN and 200 pN for CoV2 and CoV1 respectively, and the additional stability observed for CoV2 (~50 pN) might play a role in the increasing spread of COVID-19. Affiliations:
Moreira R. | - | IPPT PAN | Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Baker J.L. | - | The College of New Jersey (US) | Vargas Guzman H.A. | - | Max-Planck-Institute for Polymer Research (DE) | Poma A. | - | IPPT PAN |
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14. |
Martinez M.♦, Cooper C.D.♦, Poma Bernaola A., Guzman H.V.♦, Free energies of the disassembly of viral capsids from a multiscale molecular simulation approach,
Journal of Chemical Information and Modeling, ISSN: 1549-9596, DOI: 10.1021/acs.jcim.9b00883, Vol.60, No.2, pp.974-981, 2020Abstract: Molecular simulations of large biological systems, such as viral capsids, remains a challenging task in soft matter research. On one hand, coarse-grained (CG) models attempt to make feasible the description of the entire viral capsid disassembly. On the other hand, a permanent development of novel molecular dynamics (MD) simulation approaches like enhance sampling methods attempt to overcome the large time scales required for such simulations. Those methods have a potential for delivering molecular structures and properties of biological systems. Nonetheless, exploring the process on how a viral capsid disassembles by all-atom MD simulations has been rarely attempted. Here, we propose a methodology to analyze the disassembly process of viral capsids from a free energy perspective, through an efficient combination of dynamics using coarse-grained models and Poisson-Boltzmann simulations. In particular, we look at the effect of pH and charge of the genetic material inside the capsid, and compute the free energy of a disassembly trajectory precalculated using CG simulations with the SIRAH force field. We used our multiscale approach on the Triatoma virus (TrV) as a test case, and find that even though an alkaline environment enhances the stability of the capsid, the resulting deprotonation of the genetic material generates a Coulomb-type electrostatic repulsion that triggers disassembly. Affiliations:
Martinez M. | - | Universidad Tecnica Federico Santa Maria (CL) | Cooper C.D. | - | Universidad Tecnica Federico Santa Maria (CL) | Poma Bernaola A. | - | IPPT PAN | Guzman H.V. | - | Max-Planck-Institute for Polymer Research (DE) |
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15. |
Boopathi S.♦, Poma Bernaola A., Kolandaivel P.♦, Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment,
Journal of Biomolecular Structure and Dynamics, ISSN: 0739-1102, DOI: 10.1080/07391102.2020.1758788, pp.1-17, 2020Abstract: In the past two decades, the world has faced several infectious disease outbreaks. Ebola, Influenza A (H1N1), SARS, MERS, and Zika virus have had a massive global impact in terms of economic disruption, the strain on local and global public health. Most recently, the global outbreak of novel coronavirus 2019 (SARS-CoV-2) that causes COVID-19 is a newly discovered virus from the coronavirus family in Wuhan city, China, known to be a great threat to the public health systems. As of 15 April 2020, The Johns Hopkins University estimated that the COVID-19 affected more than two million people, resulting in a death toll above 130,000 around the world. Infected people in Europe and America correspond about 40% and 30% of the total reported cases respectively. At this moment only few Asian countries have controlled the disease, but a second wave of new infections is expected. Predicting inhibitor and target to the COVID-19 is an urgent need to protect human from the disease. Therefore, a protocol to identify anti-COVID-19 candidate based on computer-aided drug design is urgently needed. Thousands of compounds including approved drugs and drugs in the clinical trial are available in the literature. In practice, experimental techniques can measure the time and space average properties but they cannot be captured the structural variation of the COVID-19 during the interaction of inhibitor. Computer simulation is particularly suitable to complement experiments to elucidate conformational changes at the molecular level which are related to inhibition process of the COVID-19. Therefore, computational simulation is essential tool to elucidate the phenomenon. The structure-based virtual screening computational approach will be used to filter the best drugs from the literature, the investigate the structural variation of COVID-19 with the interaction of the best inhibitor is a fundamental step to design new drugs and vaccines which can combat the coronavirus. This mini-review will address novel coronavirus structure, mechanism of action, and trial test of antiviral drugs in the lab and patients with COVID-19. Keywords: coronavirus, computational simulation, coronavirus spike, ACE2 receptor, antiviral drugs, COVID-19 Affiliations:
Boopathi S. | - | other affiliation | Poma Bernaola A. | - | IPPT PAN | Kolandaivel P. | - | other affiliation |
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16. |
Senapati S.♦, Poma Bernaola A., Cieplak M.♦, Filipek S.♦, Park P.♦, Differentiating between inactive and active states of rhodopsin by atomic force microscopy in native membranes,
Analytical Chemistry, ISSN: 0003-2700, DOI: 10.1021/acs.analchem.9b00546, Vol.91, No.11, pp.7226-7235, 2019Abstract: Membrane proteins, including G protein-coupled receptors (GPCRs), present a challenge in studying their structural properties under physiological conditions. Moreover, to better understand the activity of proteins requires examination of single molecule behaviors rather than ensemble averaged behaviors. Force–distance curve-based AFM (FD-AFM) was utilized to directly probe and localize the conformational states of a GPCR within the membrane at nanoscale resolution based on the mechanical properties of the receptor. FD-AFM was applied to rhodopsin, the light receptor and a prototypical GPCR, embedded in native rod outer segment disc membranes from photoreceptor cells of the retina in mice. Both FD-AFM and computational studies on coarse-grained models of rhodopsin revealed that the active state of the receptor has a higher Young's modulus compared to the inactive state of the receptor. Thus, the inactive and active states of rhodopsin could be differentiated based on the stiffness of the receptor. Differentiating the states based on the Young's modulus allowed for the mapping of the different states within the membrane. Quantifying the active states present in the membrane containing the constitutively active G90D rhodopsin mutant or apoprotein opsin revealed that most receptors adopt an active state. Traditionally, constitutive activity of GPCRs has been described in terms of two-state models where the receptor can achieve only a single active state. FD-AFM data are inconsistent with a two-state model but instead require models that incorporate multiple active states. Keywords: nanoindentation, rhodopsin, GPCR, membrane, biophysics, AFM, active, inactive, molecular dynamics, coarse graining, go-like model Affiliations:
Senapati S. | - | Case Western Reserve University (US) | Poma Bernaola A. | - | IPPT PAN | Cieplak M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Filipek S. | - | University of Warsaw (PL) | Park P. | - | Case Western Reserve University (US) |
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17. |
Poma Bernaola A., Guzman V.H.♦, Li M.S.♦, Theodorakis P.E.♦, Mechanical and thermodynamic properties of Aβ42, Aβ40, and α-synuclein fibrils: a coarse-grained method to complement experimental studies,
Beilstein Journal of Nanotechnology, ISSN: 2190-4286, DOI: 10.3762/bjnano.10.51, Vol.10, pp.500-513, 2019Abstract: We perform molecular dynamics simulation on several relevant biological fibrils associated with neurodegenerative diseases such as Aβ40, Aβ42, and α-synuclein systems to obtain a molecular understanding and interpretation of nanomechanical characterization experiments. The computational method is versatile and addresses a new subarea within the mechanical characterization of heterogeneous soft materials. We investigate both the elastic and thermodynamic properties of the biological fibrils in order to substantiate experimental nanomechanical characterization techniques that are quickly developing and reaching dynamic imaging with video rate capabilities. The computational method qualitatively reproduces results of experiments with biological fibrils, validating its use in extrapolation to macroscopic material properties. Our computational techniques can be used for the co-design of new experiments aiming to unveil nanomechanical properties of biological fibrils from a point of view of molecular understanding. Our approach allows a comparison of diverse elastic properties based on different deformations, i.e., tensile (YL), shear (S), and indentation (YT) deformation. From our analysis, we find a significant elastic anisotropy between axial and transverse directions (i.e., YT > YL) for all systems. Interestingly, our results indicate a higher mechanostability of Aβ42 fibrils compared to Aβ40, suggesting a significant correlation between mechanical stability and aggregation propensity (rate) in amyloid systems. That is, the higher the mechanical stability the faster the fibril formation. Finally, we find that α-synuclein fibrils are thermally less stable than β-amyloid fibrils. We anticipate that our molecular-level analysis of the mechanical response under different deformation conditions for the range of fibrils considered here will provide significant insights for the experimental observations. Keywords: β-amyloid, atomic force microscopy, mechanical deformation, molecular simulation, proteins, α-synuclein Affiliations:
Poma Bernaola A. | - | IPPT PAN | Guzman V.H. | - | Max-Planck-Institute for Polymer Research (DE) | Li M.S. | - | Institute of Physics, Polish Academy of Sciences (PL) | Theodorakis P.E. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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18. |
Poma Bernaola A., Li M.S.♦, Theodorakis P.E.♦, Generalization of the elastic network model for the study of large conformational changes in biomolecules,
Physical Chemistry Chemical Physics, ISSN: 1463-9076, DOI: 10.1039/C8CP03086C, Vol.20, pp.17020-17028, 2018Abstract: The elastic network (EN) is a prime model that describes the long-time dynamics of biomolecules. However, the use of harmonic potentials renders this model insufficient for studying large conformational changes of proteins (e.g. stretching of proteins, folding and thermal unfolding). Here, we extend the capabilities of the EN model by using a harmonic approximation described by Lennard-Jones (LJ) interactions for far contacts and native contacts obtained from the standard overlap criterion as in the case of Gō-like models. While our model is validated against the EN model by reproducing the equilibrium properties for a number of proteins, we also show that the model is suitable for the study of large conformation changes by providing various examples. In particular, this is illustrated on the basis of pulling simulations that predict with high accuracy the experimental data on the rupture force of the studied proteins. Furthermore, in the case of DDFLN4 protein, our pulling simulations highlight the advantages of our model with respect to Gō-like approaches, where the latter fail to reproduce previous results obtained by all-atom simulations that predict an additional characteristic peak for this protein. In addition, folding simulations of small peptides yield different folding times for α-helix and β-hairpin, in agreement with experiment, in this way providing further opportunities for the application of our model in studying large conformational changes of proteins. In contrast to the EN model, our model is suitable for both normal mode analysis and molecular dynamics simulation. We anticipate that the proposed model will find applications in a broad range of problems in biology, including, among others, protein folding and thermal unfolding. Keywords: Free Energy, protein, elastic network, molecular dynamics, normal mode analysis Affiliations:
Poma Bernaola A. | - | IPPT PAN | Li M.S. | - | Institute of Physics, Polish Academy of Sciences (PL) | Theodorakis P.E. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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19. |
Poma Bernaola A.♦, Chwastyk M.♦, Cieplak M.♦, Elastic moduli of biological fibers in a coarse-grained model: crystalline cellulose and β-amyloids,
Physical Chemistry Chemical Physics, ISSN: 1463-9076, DOI: 10.1039/C7CP05269C, Vol.19, pp.28195-28206, 2017Abstract: We study the mechanical response of cellulose and β-amyloid microfibrils to three types of deformation: tensile, indentational, and shear. The cellulose microfibrils correspond to the allomorphs Iα or Iβ whereas the β-amyloid microfibrils correspond to the polymorphs of either two- or three-fold symmetry. This response can be characterized by three elastic moduli, namely, YL, YT, and S. We use a structure-based coarse-grained model to analyze the deformations in a unified manner. We find that each of the moduli is almost the same for the two allomorphs of cellulose but YL is about 20 times larger than YT (140 GPa vs. 7 GPa), indicating the existence of significant anisotropy. For cellulose we note that the anisotropy results from the involvement of covalent bonds in stretching. For β-amyloid, the sense of anisotropy is opposite to that of cellulose. In the three-fold symmetry case, YL is about half of YT (3 vs. 7) whereas for two-fold symmetry the anisotropy is much larger (1.6 vs. 21 GPa). The S modulus is derived to be 1.2 GPa for three-fold symmetry and one half of it for the other symmetry and 3.0 GPa for cellulose. The values of the moduli reflect deformations in the hydrogen-bond network. Unlike in our theoretical approach, no experiment can measure all three elastic moduli with the same apparatus. However, our theoretical results are consistent with various measured values: typical YL for cellulose Iβ ranges from 133 to 155 GPa, YT from 2 to 25 GPa, and S from 1.8 to 3.8 GPa. For β-amyloid, the experimental values of S and YT are about 0.3 GPa and 3.3 GPa respectively, while the value of YL has not been reported. Keywords: Tensile, shear, indentation, Atomic Force Microscopy, amyloid, cellulose Affiliations:
Poma Bernaola A. | - | other affiliation | Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Cieplak M. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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20. |
Poma Bernaola A.♦, Cieplak M.♦, Theodorakis P.E.♦, Combining the MARTINI and Structure-Based Coarse-Grained Approaches for the Molecular Dynamics Studies of Conformational Transitions in Proteins,
Journal of Chemical Theory and Computation, ISSN: 1549-9618, DOI: 10.1021/acs.jctc.6b00986, Vol.13, pp.1366-1374, 2017Abstract: The application of coarse-grained (CG) models in biology is essential to access large length and time scales required for the description of many biological processes. The ELNEDIN protein model is based on the well-known MARTINI CG force-field and incorporates additionally harmonic bonds of a certain spring constant within a defined cutoff distance between pairs of residues, in order to preserve the native structure of the protein. In this case, the use of unbreakable harmonic bonds hinders the study of unfolding and folding processes. To overcome this barrier we have replaced the harmonic bonds with Lennard–Jones interactions based on the contact map of the native protein structure as is done in Go̅-like models. This model exhibits very good agreement with all-atom simulations and the ELNEDIN. Moreover, it can capture the structural motion linked to particular catalytic activity in the Man5B protein, in agreement with all-atom simulations. In addition, our model is based on the van der Waals radii, instead of a cutoff distance, which results in a smaller contact map. In conclusion, we anticipate that our model will provide further possibilities for studying biological systems based on the MARTINI CG force-field by using advanced-sampling methods, such as parallel tempering and metadynamics. Keywords: Martini force field, protein, molecular simulation, stretching AFM, large conformational changes Affiliations:
Poma Bernaola A. | - | other affiliation | Cieplak M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Theodorakis P.E. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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21. |
Poma Bernaola A.♦, Chwastyk M.♦, Cieplak M.♦, Coarse-grained model of the native cellulose and the transformation pathways to the allomorph,
CELLULOSE, ISSN: 0969-0239, DOI: 10.1007/s10570-016-0903-4, Vol.23, pp.1573-1591, 2016Abstract: All-atom simulations are used to derive effective parameters for a coarse-grained description of the crystalline cellulose I Keywords: Cellulose, microfibril, allomorphs, structural transition, molecular dynamics, free energy Affiliations:
Poma Bernaola A. | - | other affiliation | Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Cieplak M. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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22. |
Poma Bernaola A.♦, Chwastyk M.♦, Cieplak M.♦, Polysaccharide–protein complexes in a Coarse-Grained Model,
JOURNAL OF PHYSICAL CHEMISTRY B, ISSN: 1520-6106, DOI: 10.1021/acs.jpcb.5b06141, Vol.119, pp.12028-12041, 2015Abstract: We construct two variants of coarse-grained models of three hexaoses: one based on the centers of mass of the monomers and the other associated with the C4 atoms. The latter is found to be better defined and more suitable for studying interactions with proteins described within α-C based models. We determine the corresponding effective stiffness constants through all-atom simulations and two statistical methods. One method is the Boltzmann inversion (BI) and the other, named energy-based (EB), involves direct monitoring of energies as a function of the variables that define the stiffness potentials. The two methods are generally consistent in their account of the stiffness. We find that the elastic constants differ between the hexaoses and are noticeably different from those determined for the crystalline cellulose Iβ. The nonbonded couplings through hydrogen bonds between different sugar molecules are modeled by the Lennard-Jones potentials and are found to be stronger than the hydrogen bonds in proteins. We observe that the EB method agrees with other theoretical and experimental determinations of the nonbonded parameters much better than BI. We then consider the hexaose-Man5B catalytic complexes and determine the contact energies between their the C4−α-C atoms. These interactions are found to be stronger than the proteinic hydrogen bonds: about four times as strong for cellohexaose and two times for mannohexaose. The fluctuational dynamics of the coarse-grained complexes are found to be compatible with previous all-atom studies by Bernardi et al. Keywords: Polysaccharide, protein, principal component analysis, coarse graining, molecular simulation Affiliations:
Poma Bernaola A. | - | other affiliation | Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Cieplak M. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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23. |
Chwastyk M.♦, Poma Bernaola A.♦, Cieplak M.♦, Statistical radii associated with amino acids to determine the contact map: fixing the structure of a type I cohesin domain in the Clostridium thermocellum cellulosome,
PHYSICAL BIOLOGY, ISSN: 1478-3967, DOI: 10.1088/1478-3975/12/4/046002, Vol.12, No.046002, pp.1-11, 2015Abstract: We propose to improve and simplify protein refinement procedures through consideration of which pairs of amino acid residues should form native contacts. We first consider 11 330 proteins from the CATH database to determine statistical distributions of contacts associated with a given type of amino acid. The distributions are set across the distances between the α-C atoms that are in contact. Based on this data, we determine typical radii of effective spheres that can be placed on the α-C atoms in order to reconstruct the distribution of the contact lengths. This is done by checking for overlaps with enlarged van der Waals spheres associated with heavy atoms on other amino acids.The resulting contacts can be used to identify non-native contacts that may arise during the time evolution of structure-based models. Here, the radii are used to guide reconstruction of nine missing side chains in a type I cohesin domain with the Protein Data Bank code 1AOH. We first identify the likely missing contacts and then sculpt the corresponding side chains by standard refinement tools to achieve consistency with the expected contact map. One ambiguity in refinement is resolved by determining all-atom conformational energies. Keywords: Cohesin, Go-like model, protein prediction, proteins, AFM, stretching Affiliations:
Chwastyk M. | - | Institute of Physics, Polish Academy of Sciences (PL) | Poma Bernaola A. | - | other affiliation | Cieplak M. | - | Institute of Physics, Polish Academy of Sciences (PL) |
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24. |
Poma Bernaola A.♦, Monteferrante M.♦, Bonella S.♦, Ciccotti G.♦, The quantum free energy barrier for hydrogen vacancy diffusion in Na3AlH6,
Physical Chemistry Chemical Physics, ISSN: 1463-9076, DOI: 10.1039/C2CP42536J, Vol.14, pp.15458-15463, 2012Abstract: The path integral single sweep method is used to assess quantum effects on the free energy barrier for hydrogen vacancy diffusion in a defective Na3AlH6 crystal. This process has been investigated via experiments and simulations due to its potential relevance in the H release mechanism in sodium alanates, prototypical materials for solid state hydrogen storage. Previous computational studies, which used density functional methods for the electronic structure, were restricted to a classical treatment of the nuclear degrees of freedom. We show that, although they do not change the qualitative picture of the process, nuclear quantum effects reduce the free energy barrier height by about 18% with respect to the classical calculation improving agreement with available neutron scattering data. Keywords: Alanate, proton transfer, electron hopping, Car-Parrinello MD, molecular dynamics, Free Energy, Path Integral Affiliations:
Poma Bernaola A. | - | other affiliation | Monteferrante M. | - | Sapienza University of Rome (IT) | Bonella S. | - | Sapienza University of Rome (IT) | Ciccotti G. | - | Sapienza University of Rome (IT) |
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25. |
Poma Bernaola A.♦, Site Delle L.♦, Classical to Path-Integral Adaptive Resolution in Molecular Simulation: Towards a Smooth Quantum-Classical Coupling,
PHYSICAL REVIEW LETTERS, ISSN: 0031-9007, DOI: 10.1103/PhysRevLett.104.250201, Vol.104, pp.250201-1-4, 2011Abstract: Simulations that couple different molecular models in an adaptive way by changing resolution on the fly allow us to identify the relevant degrees of freedom of a system. This, in turn, leads to a detailed understanding of the essential physics which characterizes a system. While the delicate process of transition from one model to another is well understood for the adaptivity between classical molecular models the same cannot be said for the quantum-classical adaptivity. The main reason for this is the difficulty in describing a continuous transition between two different kinds of physical principles: probabilistic for the quantum and deterministic for the classical. Here we report the basic principles of an algorithm that allows for a continuous and smooth transition by employing the path integral description of atoms. Keywords: path integral, classical-quantum coupling, adaptive resolution scheme, polymer ring, quantum structure Affiliations:
Poma Bernaola A. | - | other affiliation | Site Delle L. | - | Max-Planck-Institute for Polymer Research (DE) |
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26. |
Poma Bernaola A.♦, Site Delle L.♦, Adaptive resolution simulation of liquid para-hydrogen: Testing the robustness of the quantum-classical adaptive coupling,
Physical Chemistry Chemical Physics, ISSN: 1463-9076, DOI: 10.1039/C0CP02865G, Vol.13, pp.10510-10519, 2011Abstract: Adaptive resolution simulations for classical systems are currently made within a reasonably consistent theoretical framework. Recently we have extended this approach to the quantum-classical coupling by mapping the quantum nature of an atom onto a classical polymer ring representation within the path integral approach [Poma & Delle Site, Phys. Rev. Lett., 2010, 104, 250201]. In this way the process of interfacing adaptively a quantum representation to a classical one corresponds to the problem of interfacing two regions with a different number of effective “classical” degrees of freedom; thus the classical formulation of the adaptive algorithm applies straightforwardly to the quantum-classical problem. In this work we show the robustness of such an approach for a liquid of para-hydrogen at low temperature. This system represents a highly challenging conceptual and technical test for the adaptive approach due to the extreme thermodynamical conditions where quantum effects play a central role. Keywords: Adaptive resolution Scheme, parahydrogen, path integral, polymer ring, quantum fluid Affiliations:
Poma Bernaola A. | - | other affiliation | Site Delle L. | - | Max-Planck-Institute for Polymer Research (DE) |
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27. |
Poma Bernaola A.♦, Site Delle L.♦, Separation of variables in molecular-dynamics simulations: A criterion to estimate the quality of the approximation,
PHYSICAL REVIEW E, ISSN: 1539-3755, DOI: 10.1103/PhysRevE.78.056703, Vol.78, pp.056703-1-11, 2008Abstract: We propose a simple method to evaluate the approximation of separation of variables in molecular dynamics (MD) and related fields. It is based on a point-by-point evaluation of the difference between the true potential and the corresponding potential where the separation of variables is applied. The major advantage of such an approach is the fact that it requires only the analytical form of the potential as provided in most of the MD codes. We provide two examples of application, namely, a diatomic molecule adsorbing on a flat surface and an alkane (aliphatic) chain. Keywords: Quality control, independent DOF, coarse graining, aliphatic chain, intramolecular Affiliations:
Poma Bernaola A. | - | other affiliation | Site Delle L. | - | Max-Planck-Institute for Polymer Research (DE) |
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