MD Simulation of Protein Folding

Topics: Overview - WW domain - Publications

Overview

Proteins, made up of specified sequences of amino acid building blocks, are the workhorses of biological systems, performing most of the tasks necessary to maintain life. One of the greatest challenges in molecular biology today is that of determining how the sequence of a protein -- the exact ordering of amino acids it is composed of -- specifies its structure and function. Protein folding mechanisms have been extensively studied over the past few decades through both experimental and computational means, although the long timescales required for folding processes have meant that simulation of complete folding trajectories in explicit solvent were not possible until very recently. Instead, protein folding simulations have generally made use of coarse models, implicit solvent, or the use of very large ensembles of shorter trajectories to obtain information on the physical folding pathway.

Experimental setup

Recent advances, however, have made combined experimental and computaitonal studies of protein folding possible through the development and proteins that fold on the microsecond and even sub-microsecond timescale, and through advances in molecular dynamics simulations allowing simulation of multiple microsecond folding trajectories within a few months on modern supercomputers. Our ongoing simulations on protein folding will attempt to directly link all-atom folding simulations with folding kinetics data from the Gruebele lab at UIUC. Through simulations of a variety of protein mutants with different folding rates, we hope to gain a general understanding of factors driving protein folding.

Pin1 WW Domain

The WW domain is a fast folding, three strand beta sheet domain present in a wide variety of proteins. The WW domain from human Pin1, a proline isomerase involved in controlling cell proliferation, has been chosen as an exemplar since a number of fast-folding mutants of this protein exist and have been characterized through temperature-jump experiments. Even the fastest folding WW domain mutants require a few (3-5) microseconds to fold, which is at the very edge of the timescales currently accessible to modern all-atom molecular dynamics. Using a specially tuned version of NAMD, a 10 microsecond simulation of Pin1 WW domain was recently obtained starting from a fully unfolded state; this effort marks one of the longest single MD trajectories ever obtained, to our knowledge. Unfortunately, in this simulation the protein misfolded into an alpha helical state which remained stable throughout most of the trajectory. Continuing efforts are underway to understand whether this represents the protein becoming kinetically trapped over the course of a single simulation, or whether it is indicative of an underlying bias in the forcefield against the folded beta sheet conformation.

WW domain Folded conformation of the Pin1 WW domain. Click to view a folding trajectory.

Villin Headpiece

One of the best studied examples of fast-folding proteins, wild type villin headpiece is known to fold in 4-5 microseconds, and sub-microsecond folding mutants currently exist. Both as a test of the methods currently being employed by our lab to study protein folding, and to better understand how specific mutations to the villin headpiece accelerate its folding process, we are performing a series of folding simulations on wild type and mutant villin headpiece. The results of the first such trajectory, shown at left, illustrate folding to a native state in 5.5 microseconds. Because of its alpha helical character, villin should provide a strong contrast to the WW domain in efforts to characterize the effects of forcefields on folding simulations.

Villin headpiece Folded conformation of the villin headpiece. Click to view a folding trajectory.

Publications

Investigators

Page created and maintained by Peter Freddolino.

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