Studying the Role of Water Dynamics on the Protein Folding Mechanism Using Worldwide Distributed Computing

Stanford University, Stanford CA

Investigators

Abstract

In this project, funded jointly by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, the role of water in the folding mechanism will be investigated using computer simulation. Specifically, through large-scale massively parallel simulation, the folding of small, fast-folding proteins will be investigated on the tens of microsecond timescale. In addition, hypotheses regarding the role of water will be tested. For example, does water play a structural role in the transition state or does water merely act as a hydrophobic, dielectric medium? Previous work has suggested many possibilities, including the role of the escape of water molecules during compaction and folding, water-protein hydrogen bonding, the discrete aspects of individual water molecules and the hydrophobic effect, and lubrication effects of water. With novel simulation techniques and computational methods, these ideas will be explored and hopefully novel mechanistic aspects will be discovered. Before proteins can carry out their biological function, they must self-assemble, or "fold." Understanding how proteins fold is complicated by the nature of water. While water at first may seem like a simple liquid, it has many remarkable and complex properties. These properties, including the hydrophobic effect and hydrogen boding, can likely only be correctly understood with complex, "explicit" models for water. However, these models to date have been too complex to use in understanding long timescale behavior, such as protein folding. To overcome these timescales, a distributed computing project was created. This project, called "Folding@Home," now has approximately the power of 100,000 PCs and this vast computing power combined with novel algorithms should allow one to simulate the role of water in protein folding for the first time. Moreover, distributed computing allows for a novel "collaboration" between science and the general public. To help foster this active collaboration, the PI actively maintains a "chat room" for participants as well as many web resources to better understand proteins and protein folding. This directly connects with many of the broader impact criteria championed by NSF, including the goals of advancing discovery and understanding while promoting teaching, enhancing infrastructure for research and education (the distributed computing infrastructure itself), and broad dissemination to enhance scientific understanding (brought about and encouraged by the participation of people donating their time for the distributed computing project and their direct interest in the work being performed).