Lay summary
Different molecular processes occur over extremely broad time-scales (from fs to hours), and may involve very different numbers of atoms. Therefore, in some cases, large system sizes and long time periods place severe restrictions on the nature and type of computer simulations that can be carried out. In particular, biological systems fall into this category. Firstly, biomolecules may contain up to thousands of atoms. Secondly, biological processes may span characteristic time-scales from milliseconds to even days. In addition, these processes occur in solution, where solvent molecules can have an active role and need to be explicitly considered. Finally, dynamical effects both on short and long time scales are extremely important and must be taken into account. Thus, the predictive capability of computational models for biological systems is limited by the overall accuracy to which relevant phase-space regions are sampled. From this standpoint, a direct effort in exploration of novel techniques aimed at improving efficiency of phase-space sampling is needed to successfully develop and apply methods to soft-matter systems. Current trends in molecular simulations are driving efforts of different researchers into development of novel multi-scale techniques, able to combine coarse-grained approaches to atomistic details. In the present project, I plan to develop of a hybrid molecular mechanics / coarse-grained method, where a portion of the molecular system (i.e. a protein binding site) is treated at all-atom level, and the rest is trated at coarse-grained level. Applications to different systems of relevance in biophysics and biochemistry will be developed in parallel with the method. In particular, I will work on protein-DNA interactions, mechanisms of viral infection, allosteric phenomena, and structure-to-function relationship in multi-copper oxidases. The results achieved in the project will have a potential impact both on basic understanding of biomolecular phenomena and on biotechnological and pharmaceutical applications.In particular, the proposed applications will contribute to the development of bioengineered molecules useful in soil bioremediation, will shed light on the molecular origin of allosteric effects, which are fundamental in bio-factor expression and regulation, and will contribute to the understanding of the molecular mechanisms that regulate two major problems in medical sciences: viral infection and natural tumor suppression.