A practical method for calculating relative free energies of binding. Chiral recognition of peptidic ammonium ions by synthetic ionophores

H. Sendrowitz, D. Quentin McDonald, W. Clark Still

Research output: Contribution to journalArticlepeer-review

Abstract

A new free energy simulation method is described and applied to compute the relative binding free energies (enantioselectivity) of enantiomeric guests (2) for several chiral host molecules (1). The new simulation method is based on a previously described smart Monte Carlo method (MC(JBW)) that is here modified to interconvert diastereomeric complexes as well as to make more traditional changes in conformation. Thus the new method simulates an equilibrium between enantiomeric guests in the binding site of a host molecule and leads directly to the relative free energies of the diastereomeric complexes in a single simulation. Here we show that the MC(JBW) method originally developed for simulations of single molecules can also be applied to simulations of molecular 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 method (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 model for chloroform solvent. One form of the method is found to be more than an order of magnitude faster than traditional free energy perturbation (FEP) calculations on the same system and gives free energies of enantioselection that are in close agreement with experiment. The speed of the new method makes it a practical tool for use in designing new enantioselective host molecules.
Original languageAmerican English
Pages (from-to)9123-9127
JournalThe Journal of Organic Chemistry
Volume62
Issue number26
StatePublished - 1997

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