Combined quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations: a feasibility study

Lead Research Organisation: University of Bristol
Department Name: Chemistry


Despite the advances of science, millions of people still die every year from incurable diseases. Unfortunately, the costs of drug development are so high that the focus of medicinal research is into profitable Western diseases. To reduce the costs of developing new medicinal drugs, we would like to be able to use computers to model how a potential drug works within the body, and to use this knowledge to design new and better drugs. Building computational models like this is challenging, requiring a delicate balance between putting enough detail into the model to get realistic behaviour, and making the model as simple as possible so that it doesn't take too long to run the calculations. Until now, the majority of models used have been very simple, modelling the atoms of a drug as balls on springs. By treating the atoms as solid balls, the models neglect the atom's most chemically important part, namely the electrons. This is a severe oversight, as it is the interactions of electrons that determine whether the drug could dissolve in your blood, work its way into your cells, and bind to, and thus neutralize, the proteins of any attacking bacteria or virus. It is possible to model electrons in molecules using quantum mechanics. However, to model the entire protein/drug system using quantum mechanics would be too computationally expensive. We propose to research the use of quantum mechanics to model just the electrons that are part of, and near to, the drug molecule. The rest of the protein can still be treated by simple ball and springs models to make the calculations possible. The new methods we will develop add important extra detail, making them more realistic and better able to model how drugs interact. At the same time, this combined approach should mean that the calculations are practical to do. What makes our planned work different is that it will involve the development of a mixed model specifically tailored for medicinal drug design. Creating a mixed model for this use will require that significant challenges are overcome, and that new ways are developed to handle the interactions between the quantum mechanics part of the model with the ball on springs part.
Description EPSRC
Amount £188,950 (GBP)
Funding ID E/EP/G007705/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 03/2014
Title Sire 2007.1 
Description 2007.1 (first official) release of the Sire molecular simulation framework. This included new methods developed to calculate QM/MM free energies. 
Type Of Technology Software 
Year Produced 2007 
Open Source License? Yes  
Impact Sire is used in several pharmaceutical companies. This version of the code was used to run the simulations in "An efficient method for the calculation of quantum mechanics/molecular mechanics free energies" Christopher J. Woods, Frederick R. Manby and Adrian J. Mulholland J. Chem. Phys. 128 014109 (2008) doi:10.1063/1.2805379 The combination of quantum mechanics (QM) with molecular mechanics (MM) offers a route to improved accuracy in the study of biological systems, and there is now significant research effort being spent to develop QM/MM methods that can be applied to the calculation of relative free energies. Currently, the computational expense of the QM part of the calculation means that there is no single method that achieves both efficiency and rigor; either the QM/MM free energy method is rigorous and computationally expensive, or the method introduces efficiency-led assumptions that can lead to errors in the result, or a lack of generality of application. In this paper we demonstrate a combined approach to form a single, efficient, and, in principle, exact QM/MM free energy method. We demonstrate the application of this method by using it to explore the difference in hydration of water and methane. We demonstrate that it is possible to calculate highly converged QM/MM relative free energies at the MP2/aug-cc-pVDZ/OPLS level within just two days of computation, using commodity processors, and show how the method allows consistent, high-quality sampling of complex solvent configurational change, both when perturbing hydrophilic water into hydrophobic methane, and also when moving from a MM Hamiltonian to a QM/MM Hamiltonian. The results demonstrate the validity and power of this methodology, and raise important questions regarding the compatibility of MM and QM/MM forcefields, and offer a potential route to improved compatibility.