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Accurate energy evaluation of receptor-ligand interaction

Project Description

Drug design routinely uses existing computational methods to evaluate the interaction energy between receptor (protein) and ligand (drug) in molecular docking. The problem with these methods is that they are not reliable and accurate enough. One perspective1 squarely asks “why docking remains so primitive that it is unable to even rank-order a hit list”.
A more realistic and accurate force field will make the so-called scoring functions that docking uses more reliable. Our lab has a deep knowledge of a next-generation in-house force field called FFLUX2,3. This force field is much more realistic than a point-charge based force field such as AMBER. Moreover, FFLUX “sees the electrons” and is hence closer to the underlying quantum mechanics that ultimately governs the behaviour of all matter. FFLUX also introduces multipole moments, which is essential for accurate electrostatics4.
There is a modern and accurate energy partitioning method called Interacting Quantum Atoms (IQA)5, which offers a step change in the rigour of atomistic energy analysis. IQA is a parameter-free method that is intuitive yet very close to the quantum mechanical character of atoms themselves. Rooted in small molecules, our lab showed that IQA is feasible for systems of ~150 atoms, which is large enough to capture the essence of an active site.
An important question is how we can detect the key energy contributions that act like the total energy, in terms of an energy profile describing ligand motion. We proposed the Relative Energy Gradient (REG) method [Theor.Chem.Acc., 136, 86 (2017)], which automatically ranks atomic energy contributions by their similarity in behaving like the total system. REG was successfully used [Chem. Eur. J., 24, 11200 (2018)] for peptide hydrolysis in HIV-1 protease, thereby showing the importance of O…O and O…N through-space interactions. The computation of a pharmacophore is now possible for the first time.

Contact for further Information
Prof Popelier,

Funding Notes

Applications are invited from self-funded students. For UK/EU tuition fees are £8,750 and International are £25,500 for 2019/20 academic year.

Candidates are expected to hold (or be about to obtain) a first class honours degree (or the overseas equivalent) in chemistry or physics. Candidates with experience in machine learning or with an interest in quantum chemistry are encouraged to apply.


(1) Leach, A.; Shoichet, B. K.; Peishoff, C. E. J.Med.Chem. 2006, 49, 5851
(2) Popelier, P. L. A. Int.J.Quant.Chem. 2015, 115, 1005
(3) Popelier, P. L. A. Phys.Scr. 2016, 91, 033007
(4) Cardamone, S.; Hughes, T. J.; Popelier, P. L. A. Phys.Chem.Chem.Phys. 2014, 16, 10367
(5) Blanco, M. A.; Pendas, A. M.; Francisco, E. J.Chem.Theor.Comput. 2005, 1, 1096.

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