QM/MM free-energy perturbation and other methods to estimate ligand-binding affinities
QM/MM fri-energi perturbering och andra metoder för att uppskatta fria energier för ligand–bindning
Author
Summary, in English
Experimental drug discovery is very time-consuming, risky and comes at a huge cost, typically several billion USD per drug. Even though decades of experimental drug discovery have provided cures of many diseases, there are still diseases for which there is no effective drug available. If drug development could be performed
by theoretical and computational methods it would be of great advantage to humanity and is likely to accelerate drug discovery. One of the most promising computational methods is free-energy perturbation, which can provide estimates of protein–ligand binding affinities based on a molecular mechanics (MM)
potential. Due to limitations of empirical potential-energy functions used to describe molecular interaction, there has been some interest to perform free-energy perturbation instead at the quantum-mechanics (QM)
level of theory. To avoid the cost of performing sampling at the QM/MM level of theory, thermodynamic cycles can be employed. For this purpose, MM→QM free-energy perturbations in method space are required, but early applications have had convergence problems. In this thesis, different approaches to
converge QM/MM free-energy perturbations in method space are developed and compared to other methods to estimate protein–ligand binding affinities. Methods to obtain QM/MM energies by performing MM→QM free-energy perturbations using thermodynamic cycles are compared to direct alchemical free-energy
perturbation with a QM/MM Hamiltonian. Moreover, alternative methods to improve free-energy perturbations at the MM level of theory by charge perturbations are assessed, as well as the use of QM/MM optimised structures. Furthermore, we study also the binding entropy contribution to ligand-binding affinities for the
cancer target galectin-3. QM/MM free-energy perturbation calculations in this thesis have been converged to a precision of 1 kJ/mol. The calculated free energies agree with experimental data to within 4–6 kJ/mol, which allows for a proper ranking of lead candidates. For diastereomeric inhibitors of galectin-3, both qualitative and quantitative agreement between experimental and converged binding entropy contributions to binding affinities have been obtained with a precision of ~5 kJ/mol.
by theoretical and computational methods it would be of great advantage to humanity and is likely to accelerate drug discovery. One of the most promising computational methods is free-energy perturbation, which can provide estimates of protein–ligand binding affinities based on a molecular mechanics (MM)
potential. Due to limitations of empirical potential-energy functions used to describe molecular interaction, there has been some interest to perform free-energy perturbation instead at the quantum-mechanics (QM)
level of theory. To avoid the cost of performing sampling at the QM/MM level of theory, thermodynamic cycles can be employed. For this purpose, MM→QM free-energy perturbations in method space are required, but early applications have had convergence problems. In this thesis, different approaches to
converge QM/MM free-energy perturbations in method space are developed and compared to other methods to estimate protein–ligand binding affinities. Methods to obtain QM/MM energies by performing MM→QM free-energy perturbations using thermodynamic cycles are compared to direct alchemical free-energy
perturbation with a QM/MM Hamiltonian. Moreover, alternative methods to improve free-energy perturbations at the MM level of theory by charge perturbations are assessed, as well as the use of QM/MM optimised structures. Furthermore, we study also the binding entropy contribution to ligand-binding affinities for the
cancer target galectin-3. QM/MM free-energy perturbation calculations in this thesis have been converged to a precision of 1 kJ/mol. The calculated free energies agree with experimental data to within 4–6 kJ/mol, which allows for a proper ranking of lead candidates. For diastereomeric inhibitors of galectin-3, both qualitative and quantitative agreement between experimental and converged binding entropy contributions to binding affinities have been obtained with a precision of ~5 kJ/mol.
Department/s
Publishing year
2018-02
Language
English
Full text
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Document type
Dissertation
Publisher
Lund University, Faculty of Science, Department of Chemistry, Division of Theoretical Chemistry
Topic
- Theoretical Chemistry
Keywords
- Computer-aided drug design
- protein–ligand binding
- molecular dynamics
- free-energy perturbation
- QM/MM
- convergence
Status
Published
Supervisor
ISBN/ISSN/Other
- ISBN: 978-91-7422-577-8
Defence date
23 March 2018
Defence time
10:15
Defence place
Lecture hall A, Center for chemistry and chemical engineering, Naturvetarvägen 14, Lund
Opponent
- Bernard R. Brooks (Professor)