Development of a new method for rare event simulation

High-dimensional problems in chemistry, physics and biology pose a number of challenges to computational methodology. Computer simulations of processes in high-dimensional systems require the sampling of large parts of the configuration space. The computational effort required for direct sampling is often too large, but it can be reduced significantly if appropriate sampling strategies are chosen. For many processes of interest, the sampling effort is determined by rare events, i.e. events in the process occurring with low probability. Computational methods able to address the rare event problem can increase the sampling efficiency significantly. The project presented here has two goals: The first goal is the development of a new enhanced sampling method that combines the advantages of two complementary enhanced sampling strategies, transition path sampling and infinite swapping. The second goal is the application of this new method to the study of conformational changes in biological macromolecules. The new sampling algorithm is aimed to be suitable for the sampling of rare events, which are characteristic for functional conformational changes in proteins. However, they are also important in many other application areas, therefore the proposed method will be very general and potentially applicable to sampling problems in various areas of science. Biological macromolecules are challenging for computer simulations due to the large system size and the broad range of timescales relevant to biological processes. Many biological processes are not accessible with direct sampling at all or only in a very approximative way, therefore efficient sampling strategies are required. Knowledge about conformational changes in proteins is crucial for the understanding of protein function. The function of many proteins requires conformational changes, including structural changes upon ligand binding and unbinding as well as transitions between active and inactive structures. Two interesting systems for the study of functional conformational changes are considered in this project, including allosteric inhibition of HIV-1 protease and the structural transition between the active and the inactive conformation in Cyclin dependent kinase II.