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NBOs of the Myoglobin Complex

Large-scale Density Functional Theory

Recent progress in linear-scaling density functional theory (DFT) software allows electronic structure calculations of systems comprising many thousands of atoms to be performed on a routine basis, allowing access to typical length-scales in many biomolecules. Some of the areas in the biological sciences where DFT can play an important role include the energetics of chemical reactions in enzymes, binding of small molecules by metalloproteins, and the parameterisation of model Hamiltonians to describe energy transfer in photosynthetic light-harvesting complexes. Ongoing projects include applications in sustainable energy and medicinal Chemistry.

Selected Publications:

G. Lever, D. J. Cole, R. Lonsdale, K. E. Ranaghan, D. J. Wales, A. J. Mulholland, C.-K. Skylaris, M. C. Payne
Large-Scale Density Functional Theory Transition State Searching in Enzymes
Journal of Physical Chemistry Letters, 5, 3614 (2014) Full text

C. Weber, D. J. Cole, D. D. O'Regan, M. C. Payne
Renormalization of Myoglobin-Ligand Binding Energetics by Quantum Many-Body Effects
Proc. Natl. Acad. Sci. U.S.A., 111, 5790 (2014) Full text

D. J. Cole, A. W. Chin, N. D. M. Hine, P. D. Haynes, M. C. Payne
Toward ab initio Optical Spectroscopy of the Fenna-Matthews-Olson Complex
Journal of Physical Chemistry Letters, 4, 4206 (2013) Abstract Full text



Benzyl Oxazole Analog Bound to HIV-RT

Computational Drug Design

Optimisation of protein-ligand binding affinity is a central goal of small molecule drug discovery. A wide range of computational methods has been developed for this purpose, but free energy perturbation (FEP) is a particularly attractive option, because it provides a rigorous theoretical means to compute changes in the free energy of binding, limited only by the completeness of the sampling and the accuracy of the force field. Together with researchers in the Jorgensen lab, I have been investigating the use of the replica exchange with solute tempering (REST) enhanced sampling method in the design of inhibitors of HIV reverse transcriptase.

See the ERC-sponsored project Protein-Specific Charges for Drug Discovery for more information.

Selected Publications:

D. J. Cole, J. Z. Vilseck, J. Tirado-Rives, M. C. Payne, W. L. Jorgensen
Biomolecular Force Field Parameterization via Atoms in Molecule Electron Density Partitioning
Journal of Chemical Theory and Computation, 12, 2312 (2016) Full text

D. J. Cole, J. Tirado-Rives, W. L. Jorgensen
Molecular Dynamics and Monte Carlo Simulations for Protein-Ligand Binding and Inhibitor Design
Biochimica et Biophysica Acta (BBA) - General Subjects, 1850, 966 (2015) Full text

D. J. Cole, J. Tirado-Rives, W. L. Jorgensen
Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering
Journal of Chemical Theory and Computation, 10, 565 (2014) Abstract Full text



Natural Bond Orbitals in Chorismate Mutase

Electronic Structure Analysis

First principles calculations provide a very accurate description of the electronic structure of matter, but the electronic wave function does not provide much chemical insight into the behaviour of the system. We have implemented a range of analysis tools in the ONETEP linear-scaling DFT software to probe the electronic structure of large systems. Natural bond orbital analysis transforms ONETEP's localised basis functions into a set of Lewis-type bonding and lone-pair orbitals to give a chemical picture of bonding. Density derived electrostatic and chemical (DDEC) electron density partitioning produces atom-centred point charges that are chemically intuitive and reproduce the electrostatic potential of the QM calculation.

See the ERC-sponsored project Protein-Specific Charges for Drug Discovery for more information.

Selected Publications:

L. P. Lee, D. J. Cole, C.-K. Skylaris, W. L. Jorgensen, M. C. Payne
Polarized Protein-Specific Charges from Atoms-in-Molecule Electron Density Partitioning
Journal of Chemical Theory and Computation, 9, 2981 (2013) Abstract Full text

L. P. Lee, D. J. Cole, M. C. Payne, C.-K. Skylaris
Natural Bond Orbital Analysis in the ONETEP Code: Applications to Large Protein Systems
Journal of Computational Chemistry, 34, 429 (2013) Abstract Full text



FMO electronic structure

Protein Dynamics

The room-temperature properties of biological molecules are usually not well-represented by a single structure. We are investigating the use of constrained geometric simulations to generate an ensemble of structures for electronic structure analysis. A particularly interesting application is to light harvesting complexes in which protein dynamics is thought to be a key factor in protecting and generating quantum coherence under laboratory conditions.

Selected Publications:

A. S. Fokas, D. J. Cole, A. W. Chin
Constrained Geometric Simulation of the Fenna-Matthews-Olson Complex: The Role of Correlated Motion in Reducing Uncertainty in Excitation Energy Transfer
Photosynthesis Research, 122, 275 (2014) Full text

J. L. Kozuska, I. M. Paulsen, W. J. Belfield, I. L. Martin, D. J. Cole, A. Holt, S. M. J. Dunn
Impact of Intracellular Domain Flexibility upon Properties of Activated Human 5-HT3 Receptors
British Journal of Pharmacology, 171, 1617 (2014) Full text Commentary


Ph.D. Research

A summary of my past research interests may be found here.