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Insights into Correlated Motions and Long-Range Interactions in CheY Derived from Molecular Dynamics Simulations

Michael H. Knaggs ^*, Freddie R. Salsbury, Jr. ^*, Marshall Hall Edgell  and Jacquelyn S. Fetrow ^* 

Departments of ^* Physics and Computer Science, Wake Forest University, Winston-Salem, North Carolina; and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina

Correspondence: Address reprint requests to Jacquelyn S. Fetrow, Depts. of Physics and Computer Science, Wake Forest University, Winston-Salem, NC 27109. Tel.: 001-336-758-4957; Fax: 001-336-758-6142; E-Mail: fetrowjs{at}wfu.edu.

CheY is a response regulator protein involved in bacterial chemotaxis. Much is known about its active and inactive conformations, but little is known about the mechanisms underlying long-range interactions or correlated motions. To investigate these events, molecular dynamics simulations were performed on the unphosphorylated, inactive structure from Salmonella typhimurium and the active mimic structure (with removed) from Escherichia coli. Simulations utilized both sequences in each conformation to discriminate sequence- and structure-specific behavior. The previously identified conformational differences between the inactive and active conformations of the strand-4-helix-4 loop, which are present in these simulations, arise from the structural, and not the sequence, differences. The simulations identify previously unreported structure-specific flexibility features in this loop and sequence-specific flexibility features in other regions of the protein. Both structure- and sequence-specific long-range interactions are observed in the active and inactive ensembles. In the inactive ensemble, two distinct mechanisms based on Thr-87 or Ile-95 rotameric forms, are observed for the previously identified g+ and g– rotamer sampling by Tyr-106. These molecular dynamics simulations have thus identified both sequence- and structure-specific differences in flexibility, long-range interactions, and rotameric form of key residues. Potential biological consequences of differential flexibility and long-range correlated motion are discussed.