Monte Carlo study of ligand-protein binding energy landscapes with the weighted histogram analysis method

The thermodynamics of molecular recognition is investigated by a statistical energy landscape approach, where the temperature profile of the ligand-protein binding process is determined using the weighted histogram analysis method. The analysis reveals differences in the binding energy landscapes of two molecular fragments with the FKBP12 protein, which are reflected in their characteristic transition temperatures. The approach provides insight into the nature of transitions between unbound and bound phases of ligand-protein complexes. One molecular fragment proceeds from the unbound phase to the native complex via a short-lived intermediate at relatively high temperature. The second fragment has a significantly more rugged binding energy landscape and goes from unbound to a long-lived nonspecific bound species consisting of isoenergetic yet structurally different binding modes, and later via a second-order-like transition to the native complex. Emerging universalities in molecular recognition and protein folding mechanisms are highlighted in the context of the kinetic partitioning mechanism. (C) 1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 113-121, 1999.