Mechanical properties of the icosahedral shell of southern bean mosaic virus: A molecular dynamics study.

The mechanical properties of viral shells are crucial for viral assembly and infection. To study their distribution and heterogeneity on the viral surface, we performed atomistic force-probe molecular dynamics simulations of the complete shell of southern bean mosaic virus, a prototypical T = 3 virus, in explicit solvent. The simulation system comprised more than 4,500,000 atoms. To facilitate direct comparison with atomic-force microscopy (AFM) measurements, a Lennard-Jones sphere was used as a model of the AFM tip, and was pushed with different velocities toward the capsid protein at 19 different positions on the viral surface. A detailed picture of the spatial distribution of elastic constants and yielding forces was obtained that can explain corresponding heterogeneities observed in previous AFM experiments. Our simulations reveal three different deformation regimes: a prelinear regime of outer surface atom rearrangements, a linear regime of elastic capsid deformation, and a rearrangement regime that describes irreversible structural changes and the transition from elastic to plastic deformation. For both yielding forces and elastic constants, a logarithmic velocity dependency is evident over nearly two decades, the explanation for which requires including nonequilibrium effects within the established theory of enforced barrier crossing

Molecular dynamics force probe simulations of antibody/antigen unbinding: Entropic control and non-additivity of unbinding forces.

Unbinding of a spin-labeled dinitrophenyl (DNP) hapten from the monoclonal antibody AN02 Fab fragment has been studied by force probe molecular dynamics (FPMD) simulations. In our nanosecond simulations, unbinding was enforced by pulling the hapten molecule out of the binding pocket. Detailed inspection of the FPMD trajectories revealed a large heterogeneity of enforced unbinding pathways and a correspondingly large flexibility of the binding pocket region, which exhibited induced fit motions. Principal component analyses were used to estimate the resulting entropic contribution of ∼6 kcal/mol to the AN02/DNP-hapten bond. This large contribution may explain the surprisingly large effect on binding kinetics found for mutation sites that are not directly involved in binding. We propose that such “entropic control” optimizes the binding kinetics of antibodies. Additional FPMD simulations of two point mutants in the light chain, Y33F and I96K, provided further support for a large flexibility of the binding pocket. Unbinding forces were found to be unchanged for these two mutants. Structural analysis of the FPMD simulations suggests that, in contrast to free energies of unbinding, the effect of mutations on unbinding forces is generally nonadditive

A highly strained nuclear conformation of the exportin Cse1p revealed by molecular dynamics simulations

SummaryTo investigate the stability of the open nuclear state of the exportin Cse1p and its closing mechanism at the atomic level, we have performed multiple molecular dynamics simulations. The simulations revealed a strikingly fast transition of Cse1p from the open conformation to the closed cytoplasmic form, consistent with the proposal that Cse1p represents a “spring-loaded molecule.” The structure of the ring-shaped state obtained in the simulations is remarkably close to the crystal structure of the cytoplasmic state, though the open nuclear structure was used as the only input. The conformational change is initially driven by release of strain due to RanGTP/importin-α binding. Subsequently, a stable closed state is formed, driven by attraction of electrostatically complementary interfaces. These results are consistent with and extend previous proposals. Reverse-charge and neutral mutants remained in an open state. The simulations predict a detailed reaction pathway and resolve the role of suggested hinge regions