With Folding@home (FAH), we have the computer power to tackle challenging problems involved with protein folding. One of the interesting folding-related problems has to do with how proteins (and their conformational change) catalyze viral infection. While viral infection is not a major thrust of FAH, it has been a pilot project for several years.
We are happy to announce the publication of some of our recent FAH scientific results:
"Atomic-Resolution Simulations Predict a Transition State for Vesicle Fusion Defined by Contact of a Few Lipid Tails"
This work represents a major step forward in this project, as we can now study the process in all-atom detail and get some better sense of the role of proteins and protein conformational change in the process.
This paper describes work on the mechanism of vesicle fusion, a process involved in viral infection, the transmission of nerve impulses, and cellular secretion. In it, we have analyzed the mechanism of membrane fusion in greater detail than previously feasible, yielding predictions for how influenza may use this mechanism to enter cells. This analysis was powered by our Folding@Home donors. FAH project 2681 directly contributed to this work; we are also following up several other avenues.
A summary follows below:
Membrane fusion is a common underlying process critical to neurotransmitter release, cellular trafficking, and infection by many viruses. Proteins have been identified that catalyze fusion, and
mutations to these proteins have yielded important information on how fusion occurs. However, the precise mechanism by which membrane fusion begins is the subject of active investigation. We have used
atomic-resolution simulations to model the process of vesicle fusion and to identify a transition state for the formation of an initial fusion stalk. Doing so required substantial technical advances in
combining high-performance simulation and distributed computing to analyze the transition state of a complex reaction in a large system. The transition state we identify in our simulations involves specific
structural changes by a few lipid molecules. We also simulate fusion peptides from influenza hemagglutinin and show that they promote the same structural changes as are required for fusion in our model. We therefore hypothesize that these changes to individual lipid molecules may explain a portion of the catalytic activity of fusion proteins such as influenza hemagglutinin.