Analysis of Molecular Dynamics Simulations of Protein Folding

protein folding;molecular dynamics simulations;non-metric multidimensional scaling;principal component analysis;clustering;villin headpiece;norleucine mutant

Rajan, Aruna

关键词: protein folding;    molecular dynamics simulations;    non-metric multidimensional scaling;    principal component analysis;    clustering;    villin headpiece;    norleucine mutant;   

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美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Microsecond long Molecular Dynamics (MD) trajectories of biomolecular processes are nowpossible due to advances in computer technology. Soon, trajectories long enough to probedynamics over many milliseconds will become available. Since these timescales match thephysiological timescales over which many small proteins fold, all atom MD simulations of proteinfolding are now becoming popular. To distill features of such large folding trajectories,we must develop methods that can both compress trajectory data to enable visualization,and that can yield themselves to further analysis, such as the finding of collective coordinatesand reduction of the dynamics. Conventionally, clustering has been the most popularMD trajectory analysis technique, followed by principal component analysis (PCA). Simpleclustering used in MD trajectory analysis suffers from various serious drawbacks, namely,(i) it is not data driven, (ii) it is unstable to noise and change in cutoff parameters, and(iii) since it does not take into account interrelationships amongst data points, the separationof data into clusters can often be artificial. Usually, partitions generated by clusteringtechniques are validated visually, but such validation is not possible for MD trajectories ofprotein folding, as the underlying structural transitions are not well understood. Rigorouscluster validation techniques may be adapted, but it is more crucial to reduce the dimensionsin which MD trajectories reside, while still preserving their salient features. PCA hasoften been used for dimension reduction and while it is computationally inexpensive, beinga linear method, it does not achieve good data compression. In this thesis, I propose adifferent method, a nonmetric multidimensional scaling (nMDS) technique, which achievessuperior data compression by virtue of being nonlinear, and also provides a clear insight into the structural processes underlying MD trajectories. I illustrate the capabilities of nMDSby analyzing three complete villin headpiece folding and six norleucine mutant (NLE) foldingtrajectories simulated by Freddolino and Schulten [1]. Using these trajectories, I makecomparisons between nMDS, PCA and clustering to demonstrate the superiority of nMDS.The three villin headpiece trajectories showed great structural heterogeneity. Apart froma few trivial features like early formation of secondary structure, no commonalities betweentrajectories were found. There were no units of residues or atoms found moving in concertacross the trajectories. A flipping transition, corresponding to the flipping of helix 1 relativeto the plane formed by helices 2 and 3 was observed towards the end of the folding processin all trajectories, when nearly all native contacts had been formed. However, the transitionoccurred through a different series of steps in all trajectories, indicating that it may not bea common transition in villin folding. The trajectories showed competition between localstructure formation/hydrophobic collapse and global structure formation in all trajectories.Our analysis on the NLE trajectories confirms the notion that a tight hydrophobic coreinhibits correct 3-D rearrangement. Only one of the six NLE trajectories folded, and itshowed no flipping transition. All the other trajectories get trapped in hydrophobicallycollapsed states. The NLE residues were found to be buried deeply into the core, comparedto the corresponding lysines in the villin headpiece, thereby making the core tighter andharder to undo for 3-D rearrangement. Our results suggest that the NLE may not be afast folder as experiments suggest. The tightness of the hydrophobic core may be a veryimportant factor in the folding of larger proteins. It is likely that chaperones like GroEL actto undo the tight hydrophobic core of proteins, after most secondary structure elements havebeen formed, so that global rearrangement is easier. I conclude by presenting facts aboutchaperone-protein complexes and propose further directions for the study of protein folding.