TORSION ANGLE DYNAMICS - REDUCED VARIABLE CONFORMATIONAL SAMPLING ENHANCES CRYSTALLOGRAPHIC STRUCTURE REFINEMENT

A reduced variable conformational sampling strategy for macromolecules based on molecular dynamics in torsion angle space is evaluated using crystallographic refinement as a prototypical search problem. Bae and Haug's algorithm for constrained dynamics [Bae, D.S., Haug, E.J. A re cursive formulation for constrained mechanical system dynamics. Mech. Struct. Mach. 15:359-382, 1987], originally developed for robotics, wa s used. Their formulation solves the equations of motion exactly for a rbitrary holonomic constraints, and hence differs from commonly used a pproximation algorithms. It uses gradients calculated in Cartesian coo rdinates, and thus also differs from internal coordinate formulations. Molecular dynamics can be carried out at significantly higher tempera tures due to the elimination of the high frequency bond and angle vibr ations. The sampling strategy presented here combines high temperature torsion angle dynamics with repeated trajectories using different ini tial velocities. The best solutions can be identified by the free R va lue, or the R value if experimental phase information is appropriately included in the refinement. Applications to crystallographic refineme nt show a significantly increased radius of convergence over conventio nal techniques. For a test system with diffraction data to 2 Angstrom resolution, slow-cooling protocols fail to converge if the backbone at om root mean square (rms) coordinate deviation from the crystal struct ure is greater than 1.25 Angstrom, but torsion angle refinement can co rrect backbone atom rms coordinate deviations up to approximately 1.7 Angstrom. (C) 1994 Wiley-Liss, Inc.