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Dynamics of the Hck–SH3 domain: Comparison of experiment with multiple molecular dynamics simulations

Published online by Cambridge University Press:  01 January 2000

DAVID A. HORITA
Affiliation:
ABL-Basic Research Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201 Present address: Structural Biophysics Laboratory, Program in Structural Biology, Bldg. 538, POB B, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201.
WEIXING ZHANG
Affiliation:
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805 Present address: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
THOMAS E. SMITHGALL
Affiliation:
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805 Present address: Department Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1240 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261.
WILLIAM H. GMEINER
Affiliation:
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805
R. ANDREW BYRD
Affiliation:
ABL-Basic Research Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201 Present address: Structural Biophysics Laboratory, Program in Structural Biology, Bldg. 538, POB B, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201.
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Abstract

Molecular dynamics calculations provide a method by which the dynamic properties of molecules can be explored over timescales and at a level of detail that cannot be obtained experimentally from NMR or X-ray analyses. Recent work (Philippopoulos M, Mandel AM, Palmer AG III, Lim C, 1997, Proteins 28:481–493) has indicated that the accuracy of these simulations is high, as measured by the correspondence of parameters extracted from these calculations to those determined through experimental means. Here, we investigate the dynamic behavior of the Src homology 3 (SH3) domain of hematopoietic cell kinase (Hck) via 15N backbone relaxation NMR studies and a set of four independent 4 ns solvated molecular dynamics calculations. We also find that molecular dynamics simulations accurately reproduce fast motion dynamics as estimated from generalized order parameter (S2) analysis for regions of the protein that have experimentally well-defined coordinates (i.e., stable secondary structural elements). However, for regions where the coordinates are not well defined, as indicated by high local root-mean-square deviations among NMR-determined structural family members or high B-factors/low electron density in X-ray crystallography determined structures, the parameters calculated from a short to moderate length (less than 5–10 ns) molecular dynamics trajectory are dependent on the particular coordinates chosen as a starting point for the simulation.

Type
Research Article
Copyright
© 2000 The Protein Society

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