Damped-Dynamics Flexible Fitting

¹ The Scripps Research Institute
² University of Virginia Health System

^* To whom correspondence should be addressed. E-mail: abagyan{at}scripps.edu.

Submitted on February 25, 2008
Revised on March 19, 2008
Accepted on 5 June 2008

	Abstract

In fitting atomic structures into EM maps, it often happens that the map corresponds to a different conformation of the structure. We have developed a new methodology to handle these situations that preserves the covalent geometry of the structure and allows to model large deformations. The first goal is achieved by working in generalized coordinates (positional and internal coordinates), and the second by avoiding harmonic potentials. Instead, we use dampers ("shock absorbers") between every pair of atoms, combined with a force field that attracts the atomic structure toward incompletely occupied regions of the EM map. The trajectory obtained by integrating the resulting equations of motion converges to a conformation that, in our validation cases, was very close to the target atomic structure. Compared to current methods, our approach is more efficient and robust against wrong solutions and to overfitting, and does not require user intervention or subjective decisions. Applications to the computation of transition pathways between known conformers, homology and loop modeling, as well as protein docking, are also discussed.

Key Words: conformational change, density fitting, electron-microscopy map, protein docking, protein flexibility, transition pathway