Binding of small organic molecules to macromolecular targets: Evaluation of conformational entropy changes

The conformational entropy is the largest unfavorable effect that must be o vercome during protein folding and binding. Accurate predictions of protein stability and binding affinity require a precise way of evaluating conform ational entropy changes. Previously we implemented a computational approach aimed at estimating conformational entropy changes in peptides (D'Aquino e t al,, Proteins 1996;25:143-156; Lee et al,, Proteins 1994;20: 68-84), Here we extend this approach to estimate conformational entropy changes in mole cules of pharmaceutical interest. Calculations were carried out for a set o f 36 small organic molecules containing one dihedral angle and different fu nctional groups around the central bond. Entropy changes were calculated fo r these molecules as the difference between the entropy of the free molecul e and the entropy of the molecule when it is constrained to occupy a partic ular range of dihedrals, as in the bound state. Entropy changes for binding of larger molecules can be estimated assuming additivity on a per bond bas is. Thus, the results presented here provide an initial toolbox of conforma tional entropy values in the form of a lookup table that can be used in the estimation of entropy changes associated with binding processes of more co mplex molecules. To facilitate their use, the values were parameterized in terms of the number and type of atoms neighboring each specific dihedral, B oth methods, lookup table and parameterized equation, provide a very fast w ay of evaluating conformational entropy changes, making them suitable for f ast screening algorithms, (C) 2000 Wiley-Liss, Inc.