Molecular fractionation with conjugate caps for full quantum mechanical calculation of protein–molecule interaction energy

Abstract

A scheme to calculate fully quantum mechanical (ab initio) interaction energy involving a macromolecule like protein is presented. In this scheme, the protein is decomposed into individual amino acid-based fragments that are treated with proper molecular caps. The interaction energy between any molecule and the given protein is given by the summation of interactions between the molecule and individually capped protein fragments. This scheme, termed molecular fractionation with conjugate caps (MFCC), makes it possible and practical to carry out full quantum mechanical (ab initio) calculation of intermolecular interaction energies involving proteins or other similar biological molecules. Numerical tests performed on the interaction energies between a water molecule and three small peptides demonstrate that the MFCC method can give excellent ab initio interaction energies compared to the exact treatment in which the whole peptides are included in the calculation. The current scheme scales linearly with the atomic size of the protein and can be directly applied to calculating real protein–molecule interaction energies by using fully quantum (ab initio) methods that are otherwise impossible. The success of the current method is expected to have a powerful impact in our prediction of protein interaction energies including, e.g., protein–drug interactions.