School of Natural and Environmental Sciences

Staff Profile

Dr Daniel Cole

UKRI Future Leaders Fellow


I am a UKRI Future Leaders Fellow and lecturer in computational medicinal chemistry in the School of Natural and Environmental Sciences, Newcastle University. My research is aimed at the application of quantum mechanics to interesting questions in the biological sciences. Used alongside high performance computing, quantum mechanics has the potential to accurately predict physical and chemical properties of systems of hundreds to thousands of atoms. Much of my research is therefore aimed at using large-scale quantum mechanical calculations to develop better models for the description of protein interactions and dynamics, and ultimately for the design of pharmaceutical molecules. I also aim to understand how nature harnesses some of the more exotic characteristics of quantum mechanics to perform a desired function, evidence for which can be found in photosynthetic light-harvesting complexes in plants and bacteria, and even the proteins that transport oxygen around our bodies.

Before taking up my post at Newcastle, I held a Marie Curie international outgoing fellowship, hosted by Prof. William Jorgensen at Yale University and Prof. Mike Payne at the University of Cambridge. I have also previously worked as a research associate at the National University of Singapore and the University of Cambridge.


Area of expertise

  • Molecular and Materials Science

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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 and the aurora A kinase - TPX2 protein-protein interaction.

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 of the ONETEP linear-scaling DFT software in sustainable energy and medicinal Chemistry.

Force Field Design

Quantum mechanical calculations provide a very accurate description of the electronic structure of matter, but the sampling of conformational dynamics of biomolecules is beyond the reach of these techniques. Biomolecular dynamics are more commonly simulated using classical molecular mechanics force fields. We are developing a range of techniques to extract parameters of the classical force field directly from quantum mechanical simulations. In this way, force fields can be derived specifically for the system under study, thereby transforming their accuracy and ease-of-use. By making use of linear-scaling DFT calculations, we can even derive quantum mechanics-based force fields for entire proteins. Ongoing collaborations with the Centre for Cancer here at Newcastle and with industry will ascertain the accuracy of the new force fields in computer-aided drug design.

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.