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

在过去的几十年里，生物分子的计算模拟已经被证明是一种非常有用的方法，现在被认为是从生命的分子理解到药物发现的广泛学科中必不可少的。分子动力学是如此频繁地用于计算蛋白质在原子水平上的动力学行为，首先是由于蛋白质数据库中公开提供的大量蛋白质晶体结构，而且还因为这种方法已经很好地建立，并且优秀的软件包可以免费提供给学术生物分子科学界。然而，我们离模拟整个生物过程的细胞尺度和时间尺度还很远。在可预见的未来，这将无法通过硬件改进来解决，特别是随着计算能力的持续增长正在放缓并可能结束。因此，需要新的方法，以达到更长的时间和长度scales.This奖学金建议加入两个尖端的粗粒度蛋白质建模方法，以克服这种情况。具体来说，我将使用波动有限元分析，将蛋白质建模为受到热波动的非刚性连续体，以及多尺度粗粒化方法，旨在使用基于物理的自底向上方法描述简化的分子相互作用。一旦这种方法准备就绪，我将在适用于高性能计算的可扩展软件中实现它，并将使用这种新工具来模拟纤维蛋白网络自组装过程，这是凝块形成的关键事件之一。这是一个非常重要的生物系统，因为体内失衡与许多人类病理学有关，包括心脏和脑梗死。关于凝块结构的结构数据已经被证明与心血管疾病的临床数据相关，我将使用目前可用的实验数据来证明所提出的方法和软件的能力。接下来，进一步的模拟将阐明导致纤维蛋白聚合的缔合途径和亲和力，原纤维的侧向聚集过程，每个已知相互作用位点的作用，外部流动的影响，以及一些病理性突变体对自我的影响组装过程和凝块的最终结构。这些目标的全面实现将导致生物分子建模方法的重大进展，同时发布了一个用于中尺度生物分子模拟的通用应用程序，以及关于凝块形成过程和结构的医学相关结果。

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.