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Abstract:
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

Abstract:
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.

Abstract:
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.

Abstract:
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

Abstract:
Atomic force microscopy (AFM) is a versatile tool to characterise the mechanical properties of biological systems. However, AFM deformations are tiny, which makes impossible the analysis of the mechanical response by experiment. Here, we have employed a simulation protocol to determine the elastic properties of several biopolymers (i.e. biological fibrils). For these systems, the simulation approach is sufficient to provide reliable values for three different types of elastic deformation, i.e. tensile (YL), shear (S), and indentation (YT). Our results enable the comparison of the mechanical properties of these fibrils. In particular, we find a significant elastic anisotropy between axial and transverse directions for all systems. In addition, our methodology is sensitive to molecular packing of the fibrils. Interestingly, our results suggest 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 takes place.

Keywords:
β-amyloid, α-synuclein, nanoindentation, molecular dynamics, fibril, thermodynamics, nanomechanics, coarse graining