Exploring the Morphological Landscape of Self-Assembled Hiv-1 Proteins from a Coarse-Grained Perspective

Abstract

The self-assembly of structural proteins is central to the function of viruses. In the case of human immunodeficiency virus type-1 (HIV-1), the capsid-spacer peptide 1 (CA-SP1) domains are responsible for protein oligomerization. Under different in vitro and in vivo conditions, CA-SP1 is known to assemble into a diverse array of morphological states, including hexameric tubules, spheres, and cones; the latter two represent the physiological immature and mature virus, respectively. However, it remains unclear how the driving forces that lead to different morphological states are encoded in the CA-SP1 protein. To investigate HIV-1 assembly, our strategy is to systematically derive coarse-grained (CG) protein models in order to access experimentally-relevant spatiotemporal scales that are inaccessible to all-atom molecular dynamics (MD) simulations. Our CGMD simulations reveal that protein-protein association occurs across multiple, weak-affinity binding interfaces that are exposed in rare configurational states. We show that cofactors, salt, and membrane substrates perturb the population and affinity of pertinent protein interfaces, and consequently regulate the resultant morphology of assembled proteins. Our simulations suggest mechanisms by which viruses can simultaneously avoid kinetic traps (e.g. misaggregation) and evade immune responses. We conclude with potential directions for antiretroviral therapies.