Expanding the limits of biomolecular simulations: revealing the mechanisms of blood clot formation using Fluctuating Finite Element Analysis.

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Computational simulation of biomolecules has proven to be a very useful approach during the past few decades, and is now considered essential in broad range of disciplines ranging from the molecular understanding of life to drug discovery. Molecular dynamics is so frequently used to calculate the dynamic behaviour of proteins at the atomistic level firstly due to the large number of protein crystal structures that are publicly available in the Protein Data Base, but also because this methodology is well established, and excellent software packages are freely available to the academic biomolecular sciences community. However, we are still far from simulating cellular dimensions and time scales of entire biological processes. This will not be solved by hardware improvements in the foreseeable future, especially as the continuous increasein computational power is slowing and may come to an end. As a consequence, new methodologies are needed to reach longer time- and length-scales.This fellowship proposes to join two cutting edge methodologies in coarse-grained protein modelling to overcome this situation. Specifically, I will work with the Fluctuating Finite Element Analysis that models proteins as a non-rigid continuum subjected to thermal fluctuations, and the Multi-Scale Coarse-Graining method that aims to describe simplified molecular interactions using a physically-based bottom-up approach.Once this methodology is ready, I will implement it within a scalable piece of software suitable for High Performance Computing, and will use this new tool to simulate the fibrin network self-assembly process, one of the key events in clot formation. This is a highly important biological system, as in vivo imbalance is related to a number of human pathologies, including heart and brain infarction. Structural data on the clot architecture has been shown to correlate with clinical data on cardiovascular diseases.I will use currently available experimental data to demonstrate the capabilities of the proposed methodology and software. Next, further simulations will shed light on association pathways and affinities leading to fibrin polymerisation, on the process of lateral aggregation of protofibrils, on the role of each of the known interaction sites, on the influence of the external flow, and on the effect that some pathological mutants have on the self-assembly process and the final structure of the clot.Full accomplishment of these objectives will result in significant advances in biomolecular modelling methodology, together with the release of a general purpose application for biomolecular simulations on the mesoscale, and medically relevant results on the clot formation process and structure.