Influence of rotational energy barriers to the conformational search of protein loops in molecular dynamics and ranking the conformations

An adjustable-barrier dihedral angle potential was added as an extension to a novel, previously presented soft-core potential to study its contributio n to the effectivity of the search of the conformational space in molecular dynamics. As opposed to the conventional soft-core potential functions, th e leading principle in the design of the new soft-core potential, as well a s of its extension, the soft-core and adjustable-barrier dihedral angle (SC ADA) potential (referred as the SCADA potential), was to maintain the main equilibrium properties of the original force field. This qualifies the meth ods for a variety of a priori modeling problems without need for additional restraints typically required with the conventional soft-core potentials. In the present study, the different potential energy functions are applied to the problem of predicting loop conformations in proteins. Comparison of the performance of the soft-core and SCADA potential showed that the main h urdles for the efficient sampling of the conformational space of (loops in) proteins are related to the high-energy barriers caused by the Lennard-Jon es and Coulombic energy terms, and not to the rotational barriers, although the conformational search can be further enhanced by lowering the rotation al barriers of the dihedral angles. Finally, different evaluation methods w ere studied and a few promising criteria found to distinguish the near-nati ve loop conformations from the wrong ones. (C) 2001 Wiley-Liss, Inc.