Molecular Simulations of pH-Dependant Maturation-Associated Structural Changes in Bacteriophage HK97

Abstract

Many viruses systems respond to cellular cues by undergoing structural rearrangements. The rearrangements can involve modification of the individual subunit protein configuration and/or large scale changes to the capsid shape, size and morphology. In the latter case, these changes are largely driven by changes to the protein-protein interfaces in capsid. One of the most common cues a virus encounters during its infection process are pH modifications. The manner in which viral systems respond to pH changes is varied, however, by developing robust simulations methods for exploring these changes we will be able to examine a range of systems in the near future. In this work, we have focused on the bacteriophage HK97, as a model system for understanding large-scale, pH-induced conformational changes in virus capsids. HK97 undergoes a maturation process during which the capsid swells and facets, changing it from a spherical to a polyhedral morphology. The in-vivo process involves the packaging of the DNA genome, however, in-vitro, an analogous transformation can be achieved in the absence of DNA, just by means of pH alterations. We have employed constant-pH molecular dynamics along with string-method refinement and umbrella-sampling calculations to estimate the free-energy profiles along the maturation reaction coordinate. We have investigated how pH can influence this energy landscape by calculating pKas of titratable residues in both the mature and immature states, from which ΔΔG's of maturation can be calculated as a function of pH. By correlating key structural rearrangements with residues which have significant pKa shifts we can begin to form a mechanistic picture of how pH can trigger changes to the capsid structure and modulate the free energy landscape.