A PRACTICAL METHOD FOR CALCULATING RELATIVE FREE-ENERGIES OF BINDING - CHIRAL RECOGNITION OF PEPTIDIC AMMONIUM-IONS BY SYNTHETIC IONOPHORES

A new free energy simulation method is described and applied to comput e the relative binding free energies (enantioselectivity) of enantiome ric guests (2) for several chiral host molecules (1). The new simulati on method is based on a previously described smart Monte Carlo method (MC(JBW)) that is here modified to interconvert diastereomeric complex es as well as to make more traditional changes in conformation. Thus t he new method simulates an equilibrium between enantiomeric guests in the binding site of a host molecule and leads directly to the relative fi ee energies of the diastereomeric complexes in a single simulation . Here we show that the MC(JBW) method originally developed for simula tions of single molecules can also be applied to simulations of molecu lar complexes. We describe a further extension of this MC(JBW) method that allows it to interconvert diastereomeric complexes along with all other conformational degrees of freedom. We then use the extended met hod (termed SME for simulated mutational equilibration) to compute the free energies of enantioselection of various alanine derivatives (2) binding to ionophore 1 using the AMBER force field and the GB/SA mode l for chloroform solvent. One form of the method is found to be more t han an order of magnitude faster than traditional free energy perturba tion (FEP) calculations on the same system and gives free energies of enantioselection that are in close agreement with experiment. The spee d of the new method makes it a practical tool for use in designing new enantioselective host molecules.