Efficient calculation of two-dimensional adiabatic and free energy maps: Application to the isomerization of the C13=C14 and C15=N16 bonds in the retinal of bacteriorhodopsin

Accurate calculation of potential energy and free-energy profiles along rea ction coordinates of biological processes such as enzymatic reactions or co nformational changes is fundamental to the obtention of theoretical insight into protein function. We describe here the practical implementation of th e Automatic Map Refinement Procedure (AMRP) and two-dimensional Weighted Hi stogram Analysis Method (WHAM) for efficient computation of adiabatic poten tial energy and free-energy maps, respectively. Methods for efficiently sam pling configuration space with high-energy barriers and for removing hyster esis in the case of periodic reaction coordinates are presented. The applic ation of these techniques to the isomerization of the C13=C14 and C15=N16 b onds in the retinal of bacteriorhodopsin is described. In dark-adapted bact eriorhodopsin (bR), the retinal moiety exists in two conformers, all-trans and (13,15)cis, with the latter making similar or equal to 67% of the popul ation. This experimental free energy difference is reproduced here to withi n k(B)T. (C) 1999 John Wiley & Sons, Inc.