The use of free energy simulations as scoring functions
The use of free energy simulations as scoring functions
The combination of theories of implicit solvation, derived from the laws of classical electrostatics, with theories of free energy calculation, derived from the principles of statistical thermodynamics, is investigated. The aim of the investigation is to develop an efficient protocol for the prediction of the binding free energy of protein-ligand complexes. The Generalised Born Surface Area (GBSA) theory of implicit salvation and the Replica Exchange Thermodynamic Integration (RETI) method were selected for this work. A set of optimum parameters were derived for a GBSA force field, compatible with the General Amber Force Field (GAFF). The resulting implicit models of water were validated by assessing their ability to reproduce the salient features of the potentials of mean force for the association of several small molecules in solution. A protocol that combines efficiently GBSA potential energy function evaluation with Monte Carlo sampling was devised and validated by calculating the relative binding free energy of selected protein-ligand complexes. The implicit solvent free energy calculation protocol was then applied to determine the relative binding free energies of a set of congeneric inhibitors to two different proteins, cyclooxygenase-2 and neuraminidase. The method was found to perform as well as or better than established binding free energy calculation protocols, while converging free energy estimates faster. Established protocols can typically only calculate relative free energies between structurally similar compounds. A methodology was devised to permit the calculation of the relative free energy of structurally different compounds. The method extends thus the scope of free energy calculations. It is expected that the combination of the two methodologies will allow free energy calculations to be applied to a wider variety of problems, of direct relevance to the pharmaceutical industry.
University of Southampton
Michel, Julien
3dfda20a-a6fa-4214-8c7d-578f550b9ad7
2006
Michel, Julien
3dfda20a-a6fa-4214-8c7d-578f550b9ad7
Michel, Julien
(2006)
The use of free energy simulations as scoring functions.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The combination of theories of implicit solvation, derived from the laws of classical electrostatics, with theories of free energy calculation, derived from the principles of statistical thermodynamics, is investigated. The aim of the investigation is to develop an efficient protocol for the prediction of the binding free energy of protein-ligand complexes. The Generalised Born Surface Area (GBSA) theory of implicit salvation and the Replica Exchange Thermodynamic Integration (RETI) method were selected for this work. A set of optimum parameters were derived for a GBSA force field, compatible with the General Amber Force Field (GAFF). The resulting implicit models of water were validated by assessing their ability to reproduce the salient features of the potentials of mean force for the association of several small molecules in solution. A protocol that combines efficiently GBSA potential energy function evaluation with Monte Carlo sampling was devised and validated by calculating the relative binding free energy of selected protein-ligand complexes. The implicit solvent free energy calculation protocol was then applied to determine the relative binding free energies of a set of congeneric inhibitors to two different proteins, cyclooxygenase-2 and neuraminidase. The method was found to perform as well as or better than established binding free energy calculation protocols, while converging free energy estimates faster. Established protocols can typically only calculate relative free energies between structurally similar compounds. A methodology was devised to permit the calculation of the relative free energy of structurally different compounds. The method extends thus the scope of free energy calculations. It is expected that the combination of the two methodologies will allow free energy calculations to be applied to a wider variety of problems, of direct relevance to the pharmaceutical industry.
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Published date: 2006
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Local EPrints ID: 466575
URI: http://eprints.soton.ac.uk/id/eprint/466575
PURE UUID: 864d443b-021d-434b-8d34-923912083c13
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Date deposited: 05 Jul 2022 05:52
Last modified: 16 Mar 2024 20:47
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Author:
Julien Michel
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