General Quantum Alchemical Free Energy Simulations via Hamiltonian Interpolation

TL;DR

This paper introduces a novel quantum alchemical free energy simulation method that interpolates the electronic Hamiltonian directly, enabling efficient and accurate free energy calculations at the quantum level.

Contribution

It presents a Hamiltonian interpolation approach compatible with any electronic structure theory, requiring only one quantum calculation per MD step, unlike traditional methods.

Findings

Successfully computed free energy changes for gas-phase molecules.

Demonstrated quantum annihilation of a bonded proton for pKa estimation.

Validated the method's correctness and applicability.

Abstract

We present an implementation of alchemical free energy simulations at the quantum mechanical level by directly interpolating the electronic Hamiltonian. The method is compatible with any level of electronic structure theory and requires only one quantum calculation for each molecular dynamics step in contrast to multiple energy evaluations that would be needed when interpolating the ground-state energies. We demonstrate the correctness and applicability of the technique by computing alchemical free energy changes of gas-phase molecules, with both nuclear and electron creation/annihilation. We also show an initial application to first-principles pKa calculation for solvated molecules where we quantum mechanically annihilate a bonded proton.