Incorporating MM Polarization in hybrid QM/MM calculations

Computer simulation now plays a major role in understanding biological systems and in the design of molecules as new materials and new pharmaceuticals. In cases where it is important to study the molecules in atomic-level detail so that the distribution of electrons within the molecules can be understood, then quantum mechanics is the method of choice. In cases where the environment surrounding these molecules affects this distribution of electrons, then hybrid quantum mechanical / molecular mechanics (QM/MM) methods are used. The QM means that the molecule of interest can be studied accurately; the MM means that the environment that this molecule is in can also be taken into account, albeit at a lower level of accuracy. Within the MM part of these calculations, it is assumed that the electrons have a fixed distribution that does not change in response to the QM region of interest. Here we propose to introduce new computer methods so that the polarization of the electron distribution within the MM region can be taken into account. A simple illustration should highlight the importance of this effect. When a drug binds to an enzyme, the structure of both the drug and the enzyme must flex to accommodate each other. A similar accommodation is occurring in the spatial distribution of the electrons. Ignoring this redistribution (i.e. polarization) is therefore rather like attempting to put on a glove that is almost frozen solid. A significant part of the project will involve work to ensure that these methods can be readily used by other scientists. Applications of this new method will enable increased atomic and molecular level understanding of biological processes. The scientists that will benefit will not only include theoreticians but also enzymologists, those involved in drug design, bioinorganic chemists, photochemists, material scientists, plant scientists, spectroscopists, and those involved in biotechnology software companies.

Hybrid quantum mechanical / molecular mechanics (QM/MM) methods have now developed into powerful research tools for analysing mechanisms of both inorganic processes and enzymes. Because of the underlying quantum mechanical (QM) treatment of the region of interest, they provide the main approach to studying bond rearrangements in proteins. Advances in quantum chemistry mean that these calculations can now be carried out with reasonable accuracy. The molecular mechanics (MM) treatment of the environment ensures realistic calculations. Usually in QM/MM, the QM entity is polarized by the MM entity but the MM entity is not polarized. This asymmetry is vaguely acceptable because the focus is on the QM region. Nevertheless, there is evidence to suggest that MM polarization can be important and so here we propose to implement MM polarization into QM/MM. Here we propose to do this using induced charges, for several reasons. Firstly, they are easy to implement (so any advantages gained can be implemented in additional computer codes), secondly they are based on the electrostatic potential and so are fully consistent with the derivation of many modern force fields. Thirdly, the polarization energy determined is readily compatible with that arising from polarization of the wave function. Fourthly, the computational cost of MM polarization via induced charges is low. Optimal strategies for the efficient use of the methods will be determined. A significant part of the project will involve work to ensure that these methods can be readily used by other scientists. Applications of this new method will enable increased atomic and molecular level understanding of biological processes such as characterisation of transition states and calculation of kinetic isotope effects, understanding transition state stabilization, biological electron transfer, protein-ligand interactions, design of anti-cancer drugs and sequence specific DNA binding ligands.