Development and application of free energy methods
Development and application of free energy methods
The development of free energy simulation protocols for calculating relative binding free energies of ligands is presented in this thesis. To this end, the protein Dihydroorotate Dehydrogenase (DHODH), complexed to a highly congeneric series of compounds that show ambiguities in their binding modes, was studied in detail. To estimate the systematic error in force fields, relative free energies of hydration have been calculated using Replica-exchange Thermodynamic Integration (RETI) for sets of force field parameters and atomic partial charges in a classical molecular mechanics environment as well as a novel hybrid molecular mechanics/quantum mechanics model. The results demonstrated that all force fields and methods employed yield similar estimates of the relative free energies, while GAFF and OPLS-AA in conjunction with AM1BCC and AM1CM1A charges, respectively, performed best. To balance accuracy and ease of generating parameters, GAFF in conjunction with AM1BCC charges was selected to be the most valuable for describing the inhibitors in DHODH. To rigorously assess the thermodynamic end states for the ligands, crystal hydrates present in the binding site of DHODH have been investigated using the Just-Add-Water-molecules (JAWS) algorithm, Grand-canonical Monte Carlo (GCMC) simulations and the double-decoupling approach (DDM). These findings clearly suggested a change in hydration networks for both the inhibitors and their different binding modes, while all three approaches essentially yield identical results. This allowed us to construct free energy cycles using the single and dual topology approach in order to calculate the free energies of binding of the ligands as well as the stability of their binding modes. The results obtained were precise within the error of the methods, but not accurate, and allowed to complement the crystallographic findings.
Schopf, Patrick
ef98ae03-581f-4c14-b4ce-47523594be01
30 September 2013
Schopf, Patrick
ef98ae03-581f-4c14-b4ce-47523594be01
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Schopf, Patrick
(2013)
Development and application of free energy methods.
University of Southampton, Chemistry, Doctoral Thesis, 197pp.
Record type:
Thesis
(Doctoral)
Abstract
The development of free energy simulation protocols for calculating relative binding free energies of ligands is presented in this thesis. To this end, the protein Dihydroorotate Dehydrogenase (DHODH), complexed to a highly congeneric series of compounds that show ambiguities in their binding modes, was studied in detail. To estimate the systematic error in force fields, relative free energies of hydration have been calculated using Replica-exchange Thermodynamic Integration (RETI) for sets of force field parameters and atomic partial charges in a classical molecular mechanics environment as well as a novel hybrid molecular mechanics/quantum mechanics model. The results demonstrated that all force fields and methods employed yield similar estimates of the relative free energies, while GAFF and OPLS-AA in conjunction with AM1BCC and AM1CM1A charges, respectively, performed best. To balance accuracy and ease of generating parameters, GAFF in conjunction with AM1BCC charges was selected to be the most valuable for describing the inhibitors in DHODH. To rigorously assess the thermodynamic end states for the ligands, crystal hydrates present in the binding site of DHODH have been investigated using the Just-Add-Water-molecules (JAWS) algorithm, Grand-canonical Monte Carlo (GCMC) simulations and the double-decoupling approach (DDM). These findings clearly suggested a change in hydration networks for both the inhibitors and their different binding modes, while all three approaches essentially yield identical results. This allowed us to construct free energy cycles using the single and dual topology approach in order to calculate the free energies of binding of the ligands as well as the stability of their binding modes. The results obtained were precise within the error of the methods, but not accurate, and allowed to complement the crystallographic findings.
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Published date: 30 September 2013
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University of Southampton, Chemistry
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Local EPrints ID: 366938
URI: http://eprints.soton.ac.uk/id/eprint/366938
PURE UUID: 7271a9d7-1a89-4d7a-af53-3d3d986ab579
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Date deposited: 21 Oct 2014 15:40
Last modified: 15 Mar 2024 02:46
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Author:
Patrick Schopf
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