Modeling protein conformational changes by iterative fitting of distance constraints using re-oriented normal modes

¹ NIH
² National Institutes of Health

^* To whom correspondence should be addressed. E-mail: zhengwj{at}helix.nih.gov.

Submitted on October 27, 2005
Revised on December 1, 2005
Accepted on 7 March 2006

	Abstract

Recently, we have developed a normal modes based algorithm that predicts the direction of protein conformational changes given the initial state crystal structure together with a small number of pair-wise distance constraints for the end state. Here we significantly extend this method to accurately model both the direction and amplitude of protein conformational changes. The new protocol implements a multi-steps search in the conformational space that is driven by iteratively minimizing the error of fitting the given distance constraints and simultaneously enforcing the restraint of low elastic energy. At each step, an incremental structural displacement is computed as a linear combination of the lowest 10 normal modes derived from an elastic network model, whose eigenvectors are re-orientated to correct for the distortions caused by the structural displacements in the previous steps. We test this method on a list of 16 pairs of protein structures for which relatively large conformational changes are observed (RMSD>3Å), using up to 10 pair-wise distance constraints selected by a fluctuation analysis of the initial state structures. This method has achieved a near-optimal performance in almost all cases, and in many cases the final structural models lie within RMSD of 1~2Åfrom the native end state structures.

Key Words: conformational change, distance constraint, elastic network model, normal modes analysis

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