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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:
Molecular simulation 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 capsids. On the other hand, novel development of molecular dynamics (MD) simulation approaches, like enhance sampling which attempt to overcome the time scales required in biophysics. Those methods have a potential for delivering molecular structures and properties of biological systems. Nonetheless, exploring the process on how a capsid disassembles by all-atom MD simulations has been rarely attempted. Here, we propose a methodology to analyze the disassembly process of viral capsids quantitatively. 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 by combining CG simulatiosn to a Poisson-Boltzmann solver. We employ such multiscale approach on the triatoma virus as a test case, and find that even though an alkaline environment enhances the stability of the capsid, the resulting deprotonation of the internal solvent generates an electrostatic repulsion that triggers disassembly.

Keywords:
Poisson Boltzmann, free energy, viral capsid, molecular dynamics, multiscale simulation, coarse graining, pH, protein assemblies