Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Molecular Dynamics Simulation Studies of Protein Sectors: Motional Correlations
Protein "sectors", sparse, hierarchical networks of amino acid residues that have been indicated to be key elements of cooperativity in structure and function, have been obtained to date from evolutionary correlation matrices using Statistical Coupling Analysis (SCA). (Halabi, et al., 2009; Lockless and Ranganathan, 1999; Reynolds, et al., 2011) In this study, all-atom molecular dynamics (MD) computer simulations have been carried out to investigate the nature of protein sectors at the sub-molecular level. Our focus in this study is on the single domain protein PSD95-PDZ3, which has served as the benchmark for a number of previous studies of prediction methods of functionally important amino acid positions. Motional correlation matrices of amino acids obtained from MD on PDZ3 are analyzed using spectral decomposition in a manner similar to that used to analyze positional correlation matrices in SCA, leading by analogy to "MD sectors" of a protein. We find that MD and SCA sectors coincide in 15/20 residue positions of PDZ3, and MD sectors likewise includes 10/13 amino acids of functional significance in the peptide binding pocket. The MD sectors also coincide with 15/20 of the positions of mutational sensitive residues determined experimentally, which serves to independently validate the idea. Both SCA and MD sectors include residues of a groove distal to the binding pocket observed to be implicated in single domain allosterism. The agreement in the composition of SCA and MD sectors provides leading support of the idea that SCA sectors may be related to MD motional fluctuations. This must be demonstrated in a larger set of systems to make any general conclusions, but the results to date indicate such studies are warranted. The idea of MD sectors opens up a potentially valuable new approach to the theoretical analysis of cooperativity and allosterism from MD simulations.
Lockless, S.W. and Ranganathan, R. (1999) Evolutionarily conserved pathways of energetic connectivity in protein families, Science, 286, 295-299.
Reynolds, K.A., McLaughlin, R.N. and Ranganathan, R. (2011) Hot spots for allosteric regulation on protein surfaces, Cell, 147, 1564-1575.
Departments of Chemistry