Characterising and Controlling Rare Event Dynamics

Theory and simulation are cornerstones of molecular science, guiding, informing, and interpreting experiments. Some simulations are performed to test the practicality of costly laboratory work, while other calculations may provide information that is not accessible experimentally. Applications cover a diverse range of activities, from drug design in the pharmaceutical industry, through surface catalysis, to predicting the behaviour of soft matter in materials such as liquid crystals, which are used in display technology.For computer simulations to be useful we must achieve some level of confidence in the predictions that are made. Achieving useful accuracy depends on both a sufficiently faithful representation of the interatomic or intermolecular interactions, and on whether the calculated quantities reflect the conditions of the experiment in a statistically meaningful way. Our proposal addresses the latter issue, namely how to sample events of interest that rarely occur on the accessible time scale of simulations. Calculating a meaningful average for some property of interest is impossible for many problems of great contemporary importance using conventional methods. Examples include chemical reactions and changes of structure or phase that correspond to a large barrier on the potential or free energy surface. Conventional simulations of such systems will spend all or most of the available computer time waiting for the barrier to be crossed, and may miss the key transition entirely. More sophisticated simulation techniques are therefore needed, which sample the events of interest directly.Various complementary approaches have been suggested to address this rare events problem and extend computer simulations to larger systems and longer time scales. We propose to combine two of the most successful methods, one that is based on geometry optimisation, and the other on explicit dynamics, to produce a hybrid methodology that is efficient enough to treat mesoscopic problems. The geometry optimisation approach can treat events that are arbitrarily slow, because the barriers in question are calculated directly. Rate constants can then be evaluated using well known tools from unimolecular rate theory, which involves a series of approximations. By combining the pathways determined by geometry optimisation with explicit dynamics we aim to produce much more accurate rate constants and extend the domain accessible to simulation to treat far more complex systems.Two important applications will be considered. First we will analyse the pathways for nucleation in a wide variety of bulk systems, including models that form glasses, liquid crystals, and granular material. Our most ambitious objective is to use this knowledge to gain kinetic control of nucleation. The ability to predict the outcome of nucleation, and change conditions accordingly, would be immediately useful to pharmaceutical companies and to the manufacture of materials based upon glasses or liquid crystals. The ability to describe and predict the ageing properties of glassy materials will immediately find a number of important applications.The second application we would consider involves the design of a molecular motor from mesoscopic building blocks. Here we would seek to determine general design principles that govern the efficiency of converting chemical energy into available work. Hence we would guide experiments in the choice of molecular components to produce an efficient motor, including characteristics of the intermolecular interaction governed by shape, charge, etc.

Our proposal concerns development of new methodology to enable computer simulation techniques to be used for systems at the cutting edge of current research in nanotechnology, materials design, biotechnology and pharmaceuticals. Computer simulation is now a standard technique that is used throughout molecular science, both to provide insight at a level of detail or generality that is not available from experiment, or to save costly laboratory resources. Unfortunately, the complexity of systems at the forefront of contemporary interest is such that standard simulation techniques often cannot address the required length or time scales. By combining two of the most successful methods for treating such rare events we will greatly extend the boundaries for prediction and analysis of such systems. WHO WILL BENEFIT? In the short term our new methodology and computer codes will benefit groups working on computer modeling of molecular systems throughout universities and industry. In the medium and longer term the fruits of this new research should be of general benefit to society, with potential impacts in fields ranging from human health care to the development of novel materials that could feature in day-to-day life. HOW WILL THEY BENEFIT? The short term benefits to the computer simulation community will consist of new tools that facilitate computational analysis of more complex systems of direct relevance to experiment. Rare events are bottlenecks for contemporary research efforts in the simulation of biomolecules, with implications for drug design, nanotechnology, and design of new materials. In the medium to longer term the capability to simulate the folding or misfolding of proteins and nucleic acids at a coarse-grained or fully atomistic level could provide the insight required for novel pharmaceutical strategies. Characterizing pathways and kinetics for nucleation in glassy systems and liquid crystals will provide the insight required for kinetic control and rational design of materials with specific optoelectronic properties, including new display technologies. All these ambitions fall within the general area of computer guided nanotechnology, which is a field currently expanding on a daily basis. In the future it may be possible to design nanoscale devices such as molecular motors. Our proposal will lay some key foundations for this field by characterizing the conditions that provide an optimum powerstroke. WHAT WILL BE DONE TO ENSURE THAT THEY HAVE THE OPPORTUNITY TO BENEFIT? Our new theoretical techniques and applications will be published in peer-reviewed journals with high impact factors. We have a very strong track record in this regard, with numerous publications in journals such as Science, Nature, and Phys. Rev. Lett. We will also disseminate our results at meetings, ranging from large international conferences to informal workshops. Both applicants receive many more invitations to speak at international meetings than they can fulfill, and select the venues that are likely to achieve the greatest impact in the simulation community. We also contribute invited reviews and feature articles to leading journals on a regular basis. To ensure that our new methodology can be used by other groups without delay we will provide full implementations of all the new algorithms in public domain, open source, computer codes. The applicants have extensive experience of supporting such programming efforts, having distributed several programs under the Gnu public licence for well over a decade. These programs are used by many research groups around the world, and are supported by web sites that provide full documentation and examples of input and output. We also have experience of sharing our methodology with industry, including drug discovery companies such as Evotec OAI, and giants of the chemical industry, such as Shell. We are actively pursuing new projects with industry in several directions.