Conformational dynamics of RNA-peptide binding: A molecular dynamics simulation study

¹ School of Biological Sciences, Nanyang Technological University, Singapore
² University of Frankfurt

^* To whom correspondence should be addressed. E-mail: stock{at}theochem.uni-frankfurt.de.

Submitted on June 28, 2005
Revised on August 17, 2005
Accepted on 16 September 2005

	Abstract

Molecular dynamics (MD) simulations of the binding of the heterochiral tripeptide KkN to the trans-activation responsive (TAR) RNA of HIV-1 are presented, using an all-atom force field with explicit water. To obtain starting structures for the TAR-KkN complex, first semirigid docking calculations were performed which employ an NMR structure of free TAR RNA. The MD simulations show that the starting structures in which KkN binds to the major groove of TAR (as it is the case for the Tat-TAR complex of HIV-1) are unstable. On the other hand, the minor-groove starting structures are found to lead to several binding modes, which are stabilized by a complex interplay of stacking, hydrogen bonding, and electrostatic interactions. While the ligand does not occupy the binding position of Tat protein, it is shown to hinder the interhelical motion of free TAR RNA. The latter is presumably necessary to achieve the conformational change of TAR RNA to bind Tat protein. Considering the time evolution of the trajectories, the binding process is found to be ligand-induced and cooperative. That is, the conformational rearrangement only occurs in the presence of the ligand and the concerted motion of the ligand and a large part of the RNA binding site is necessary to achieve the final low-energy binding state.

Key Words: Molecular dynamics simulation, RNA-peptide binding, TAR RNA, cooperative conformational transition, global interhelical motion, induced fit

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