Systematic Dissociation Pathway Searches Guided by Principal Component Modes.

We introduce a novel method, Pathway Search guided by Internal Motions (PSIM), that efficiently finds molecular dissociation pathways of a ligand-receptor system with guidance from principal component (PC) modes obtained from molecular dynamics (MD) simulations. Modeling ligand-receptor dissociation pathways can provide insights into molecular recognition and has practical applications, including understanding kinetic mechanisms and barriers to binding/unbinding as well as design of drugs with desired kinetic properties. PSIM uses PC modes in multilayer internal coordinates to identify natural molecular motions that guide the search for conformational switches and unbinding pathways. The new multilayer internal coordinates overcome problems with Cartesian and classical internal coordinates that fail to smoothly present dihedral rotation or generate nonphysical distortions. We used HIV-1 protease, which has large-scale flap motions, as an example protein to demonstrate use of the multilayer internal coordinates. We provide examples of algorithms and implementation of PSIM with alanine dipeptide and chemical host-guest systems, 2-naphthyl ethanol-β-cyclodextrin and tetramethylammonium-cryptophane complexes. Tetramethylammonium-cryptophane has slow binding/unbinding kinetics. Its residence time, the length to dissociate tetramethylammonium from the host, is ∼14 s from experiments, and PSIM revealed 4 dissociation pathways in approximately 150 CPU h. We also searched the releasing pathways for the product glyceraldehyde-3-phosphate from tryptophan synthase, and one complete dissociation pathway was constructed after running multiple search iterations in approximately 300 CPU h. With guidance by internal PC modes from MD simulations, the PSIM method has advantages over simulation-based methods to search for dissociation pathways of molecular systems with slow noncovalent kinetic behavior.