Development and application of a QM/MM method for free energy calculations

Abstract

In this thesis, a simplified Quantum Mechanics/Molecular Mechanics (QM/MM) method has been developed, which incorporates Density Functional Theory (DFT) and Free Energy Perturbation (FEP) to calculate QM/MM corrections for classically obtained MM free energies. This method has been applied to the calculation of hydration free energies and protein-ligand binding free energies. The hydration free energy study showed that for small organic compounds the QM/MM method could perform as well as standard MM.

Further analysis highlighted that implementing QM/MM appeared to over-polarise for compounds with hydrogen bonding moieties. This over-polarisation was caused by the embedding technique utilised. Hence, the embedding strategy was adapted to utilize a Gaussian blurring approach, which enabled the minimisation impact of this over-polarisation. For the protein-ligand studies three proteins were investigated; COX-2, neuraminidase and CDK2. The results from these studies showed that the QM/MM method obtain less accurate results than conventional MM. This has been attributed to several factors, including; too simplistic embedding techniques leading to over polarisation for extremely polar protein-ligand systems (neuraminidase) and poor agreement for protein-ligand systems with small pocket sizes. Also, GCMC simulations have identified that erroneous system setup for CDK2 is the root cause of extremely poor correlation in both MM and QM/MM free energy studies.

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Identifiers

ORCID for Jonathan W. Essex: orcid.org/0000-0003-2639-2746

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