Machine learning augmented molecular simulation pipelines for modelling allosteric modulation of protein function

该项目将专注于开发基于分子模拟和机器学习的计算方法，以预测配体与蛋白质表面的结合将如何调节其生物功能。这种能力可能有助于合理设计蛋白质功能的变构调节剂，这在药物发现中具有重要意义。这项工作建立在马尔可夫状态建模方法和炼金术自由能计算方法的基础上，米歇尔研究小组最近开发了这些方法来模拟蛋白质结构(化学)的大规模构象变化。SCI。，11,2670-2680,2020)，并估计蛋白质-配体结合亲和力(Chem.SCI。，13,5220-5229,2022)。在整个项目中，将有机会与对这种方法感兴趣的制药公司互动。

This project will focus on developing computational methodologies grounded in molecular simulation and machine learning for predicting how the binding of a ligand to the surface of a protein will modulate its biological function. Such capability may facilitate the rational design of allosteric modulators of protein function which of enormous importance in drug discovery. This work builds on Markov State Modelling methodologies and alchemical free energy calculation methodologies that the Michel research group has recently developed to simulate large scale conformational changes in protein structures (Chem. Sci. , 11, 2670-2680, 2020) and to estimate protein-ligand binding affinities (Chem. Sci. , 13, 5220-5229, 2022). Throughout the project there will be opportunities to interact with pharmaceutical companies interested in such methodologies.