Development and application of CHARMM's hybrid QM/MM reaction path methods

H. Lee Woodcock III, hlwood@nih.gov and Bernard R. Brooks,
brb@nih.gov. Laboratory of Computational Biology, National Heart, Lung and Blood
Institute, National Institutes of Health, 50 South Dr. MSC 8014, Bethesda, MD
20892-8014

Recent work will be presented on extending CHARMM's pathway searching facilities
(e.g. the replica path method (RPM) and nudged elastic band (NEB) method) to
work with hybrid SCCDFTB QM/MM coupled potentials. The replica path method
involves the definition of a reaction path via replication of a set of
macromolecular atoms. An "important" subset of these replicated atoms is
restrained with a penalty function based on weighted root-mean-square
rotation/translation best-fit distances between adjacent (i ± 1) and next
adjacent (i ± 2) pathway steps. An independent subset of the replicated atoms
may be treated quantum mechanically. This treatment can be performed in a highly
parallel manner in which large numbers of processors can be efficiently
employed. In addition, ongoing work is being done that seeks to develop new
methods for computing free energies of reactions. This effort entails extending
the Replica Path method to sample orthogonal directions of conformational space
while maintaining the viability of a well described reference pathway. This is
accomplished by applying holonomic planar restraints such that pathway point i
will be equidistant from points (i + 1) and (i - 1). This allows for extremely
efficient, highly parallel, sampling of an entire reaction pathway via either
classical or hybrid QM/MM potentials.