Understanding biomolecular association from large-scale first principles quantum mechanical simulations

Intermolecular association underpins most biological processes, such as the complex interactions between DNA and proteins during cell division in healthy cells but also in diseases such as cancers, or the apparently irreversible assembly of amyloid proteins in Alzheimer's and other age-related diseases. As a consequence, major research effort is targeted towards understanding and controlling biomolecular association, including developing drugs that will prevent or cure pathologies. The aim is to make the 'health span' as long as the ever increasing life span and achieve 'lifelong health and well-being', a strategic research priority of the BBSRC. Nevertheless, we are still often not able to predict biomolecular association with accuracy relevant to real applications. The point is that biomolecular interactions are determined by the electronic rearrangements that take place upon association (e.g. charge transfer and polarisation) which vary in strength, but not taken well into account by the force field approaches that are usually employed, with parameters tuned to particular situations. Quantum mechanical calculations from first principles ('ab initio') overcome these limitations as they include the electrons explicitly; however they have steep (cubic) computational scaling with system size and cannot be used in molecules with more than a few hundred atoms. The ONETEP program, developed by Dr Skylaris and his collaborators, is able to overcome this limitation as it is based on a novel reformulation of quantum theory which scales linearly with the number of atoms without loss of accuracy. We have performed calculations with ONETEP on systems with up to 50,000 atoms. The aim of this project, which will be supported by Boehringer Ingelheim (BI), is to overcome the shortcomings of force fields by using quantum calculations to treat the entire system, unlike previous attempts where only a small part of the system has been quantum. Since October 2008 BI have supported a PhD student through the BBSRC ICS scheme who has made the first steps towards this goal by showing that in certain well-known proteins a quantum description of the whole system can be essential as it leads to significant improvements in free energies of binding when compared to the same simulation protocol with force fields. Encouraged by these early successes, we want to apply this approach on more challenging pharmaceutical systems, together with new tools that are coming out as the functionality of ONETEP is currently enhanced by 3 postdoctoral researchers working in Southampton, Cambridge and Imperial College London. These new tools will include an implicit solvation model directly within the self-consistent quantum calculation, more accurate van der Waals interactions, and techniques for large-scale ab initio molecular dynamics simulations with direct calculation of free energies of binding. A parallel strand of the work will employ the multiple thermodynamic cycles approach of workers such Arieh Warshel (USC), Adrial Mulholland (Bristol) and Jonathan Essex (Southampton, with whom we collaborate) whereby 'classical' and 'quantum' systems are considered as different thermodynamic states and rigorous approaches for free energy changes (e.g. free energy perturbation theory) are used to make the transition between these states, using statistical acceptance tests to ensure that each 'move' is valid. For the first time we will apply such approaches by having the 'quantum' be the entire system, rather than a small portion of it, thus having a consistent representation. It has been a great pleasure so far to work with BBSRC and BI as it has enabled us to make the first steps in evaluating new and potentially very powerful simulation technologies. Our continued collaboration will ensure impact of direct relevance to the pharmaceutical industry which could move well outside the biomolecular association domain all the way to systems biology.