On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder

Viral diseases continue to contribute to leading causes of death around the world and are annually responsible for significant morbidity and mortality. Many envelope viruses infect cells through the use of fusion proteins, surface proteins which are responsible for fusing the viral and host membranes through large scale conformational transitions. Although pre-fusion and post-fusion structures have been experimentally determined for many viral fusion proteins, specific structural details about how they transition between these states have remained challenging to probe both experimentally and computationally. Even with recent computational advances, acquiring equilibrium distributions of the entire functional landscape through standard molecular dynamics calculations is not currently feasible. In this body of work, we employ structure based models to analyze the conformational dynamics of a range of viral fusion proteins. Structure based models have rigorous mathematical roots in the language of energy landscape theory and have been successfully applied to many problems in folding, allostery, and functional motions of biomolecules. These models take experimental structures as an input and make them explicit energy minima in the Hamiltonian. We construct energy functions for several viral fusion proteins which simultaneously include all interactions from the pre- and post-fusion structures and observe their time evolution. We first analyze Influenza A Hemagglutinin, where we show that Hemagglutinin can transition by two dominant pathways. Both pathways are characterized by an early order-disorder transition in a characteristic hairpin region and breaking of the threefold symmetry present in the prefusion structure. Late stage N-C terminal zipping completes the transition. This picture is in contrast with the standard spring-loaded view of Hemagglutinin mediated fusion, where an early loop to helix transition drives the transition. We extend this analysis to a survey of other Class I viral fusion proteins and show that they all share the same global mechanistic features observed in Hemagglutinin. Finally, we employ a similar model to investigate Class II Dengue Envelope dimers and show that symmetry in the potential gives rise to a dynamic, entropically stabilized intermediate state. Collectively, these results are suggestive that viruses take advantage of conformational flexibility and disordered intermediate ensembles to facilitate viral entry.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Natural Sciences

Grantor

Rice University

Year dc:date.issued

2018

Author dc:creator

• Eddy, Nathanial Reed

Advisor dc:contributor.advisor

• Onuchic, José N

• viral fusion
• conformational dynamics
• protein folding
• hemagglutinin

Statement dc:rights

• Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1911/105758

OAI identifier oai:identifier

oai:repository.rice.edu:1911/105758