TY - JOUR
T1 - Configurational Entropy in Protein-Peptide Binding:. Computational Study of Tsg101 Ubiquitin E2 Variant Domain with an HIV-Derived PTAP Nonapeptide
AU - Killian, Benjamin J.
AU - Kravitz, Joslyn Yudenfreund
AU - Somani, Sandeep
AU - Dasgupta, Paramita
AU - Pang, Yuan Ping
AU - Gilson, Michael K.
N1 - Funding Information:
This publication was made possible by grant no. GM61300 (M.K.G.) from the National Institute of General Medical Sciences of the National Institutes of Health and grant no. W81XWH-08-1-0154 (Y.P.P.) from the U.S. Army Medical Research Acquisition Activity. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of General Medical Sciences.
PY - 2009/6/5
Y1 - 2009/6/5
N2 - Configurational entropy is thought to influence biomolecular processes, but there are still many open questions about this quantity, including its magnitude, its relationship to molecular structure, and the importance of correlation. The mutual information expansion (MIE) provides a novel and systematic approach to extracting configurational entropy changes due to correlated motions from molecular simulations. We present the first application of the MIE method to protein-ligand binding using multiple molecular dynamics simulations to study the association of the ubiquitin E2 variant domain of the protein Tsg101 and an HIV-derived nonapeptide. This investigation utilizes the second-order MIE approximation, which accounts for correlations between all pairs of degrees of freedom. The computed change in configurational entropy is large and has a major contribution from changes in pairwise correlation. The results also reveal intricate structure-entropy relationships. Thus, the present analysis suggests that in order for a model of binding to be accurate, it must include a careful accounting of configurational entropy changes.
AB - Configurational entropy is thought to influence biomolecular processes, but there are still many open questions about this quantity, including its magnitude, its relationship to molecular structure, and the importance of correlation. The mutual information expansion (MIE) provides a novel and systematic approach to extracting configurational entropy changes due to correlated motions from molecular simulations. We present the first application of the MIE method to protein-ligand binding using multiple molecular dynamics simulations to study the association of the ubiquitin E2 variant domain of the protein Tsg101 and an HIV-derived nonapeptide. This investigation utilizes the second-order MIE approximation, which accounts for correlations between all pairs of degrees of freedom. The computed change in configurational entropy is large and has a major contribution from changes in pairwise correlation. The results also reveal intricate structure-entropy relationships. Thus, the present analysis suggests that in order for a model of binding to be accurate, it must include a careful accounting of configurational entropy changes.
KW - correlation
KW - multiple molecular dynamics simulation (MMDS)
KW - mutual information expansion (MIE)
KW - thermodynamics
KW - translational/rotational entropy
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U2 - 10.1016/j.jmb.2009.04.003
DO - 10.1016/j.jmb.2009.04.003
M3 - Article
C2 - 19362095
AN - SCOPUS:65549109031
SN - 0022-2836
VL - 389
SP - 315
EP - 335
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 2
ER -