A multi-scale approach for macromolecular systems
Doctor of Philosophy
Understanding biomolecular dynamics at different time and length scales is key to solving major problems in molecular biology and physical-chemistry. Because of the multiple scales that intrinsically coexist in biological macromolecules, the field has evolved through different paths, each focusing on different fixed resolutions. This thesis focuses on developing realistic models to describe complex biomolecular land-scapes at the mesoscale level, and a procedure to bridge different levels of molecular description for liquid water. Toward this goal, we have proposed a realistic coarse-grained protein model and a technique to incorporate experimental data into the model to examine the long time-scale phenomenon of protein folding/misfolding. We have shown that simulations with this simplified protein representation can be used as a predictive tool for misfolding and aggregation of proteins. Moreover, we have developed a coarse-grained model and an analytical theory to study another long time-scale phenomenon in biology: the translocation of DNA and RNA through nanopores. We have shown that our approach to the translocation process reproduces quantitatively, for the first time, all the experimentally observed trends and scaling behaviour, and provides insight into the different regimes present in the system. Modeling explicit water is crucial for realistic biomolecular simulations, but is typically not computationally feasible. To overcome the computational impasse, we have proposed a coarse-grained water model that can reproduce remarkably well the behaviour of liquid water at physiological conditions, and a spatially adaptive procedure to change the molecular resolution of water on-the-fly from a coarse-grained to an all-atom representation. This adaptive multi-scale approach bridges the gap between the time and length scales accessible to simulations without losing atomistic detail on physically relevant regions.
Physical chemistry; Condensed matter physics; Biophysics