ABSTRACT
A distance constraint model (DCM) is presented that identifies flexible regions within protein structure consistent with specified thermodynamic condition. The DCM is based on a rigorous free energy decomposition scheme representing structure as fluctuating constraint topologies. Entropy non-additivity is problematic for naive decompositions, limiting the success of heat capacity predictions. The DCM resolves non-additivity by summing over independent entropic components determined by an efficient network-rigidity algorithm. A minimal 3-parameter DCM is demonstrated to accurately reproduce experimental heat capacity curves. Free energy landscapes and quantitative stability-flexibility relationships are obtained in terms of global flexibility. Several connections to experiment are made.
Subject(s)
Protein Conformation , Proteins/chemistry , Drug Stability , Entropy , Hydrogen Bonding , Models, Molecular , Stress, Mechanical , ThermodynamicsABSTRACT
We discuss here the implementation of the Weighted Ensemble Brownian (WEB) dynamics algorithm of Huber and Kim in the University of Houston Brownian Dynamics (UHBD) suite of programs and its application to bimolecular association problems. WEB dynamics is a biased Brownian dynamics (BD) algorithm that is more efficient than the standard Northrup-Allison-McCammon (NAM) method in cases where reaction events are infrequent because of intervening free energy barriers. Test cases reported here include the Smoluchowski rate for association of spheres, the association of the enzyme copper-zinc superoxide dismutase with superoxide anion, and the binding of the superpotent sweetener N-(p-cyanophenyl)-N'-(diphenylmethyl)-guanidinium acetic acid to a monoclonal antibody fragment, NC6.8. Our results show that the WEB dynamics algorithm is a superior simulation method for enzyme-substrate reaction encounters with large free energy barriers.
