Modelling variable protonation states in protein-ligand systems

分子模拟现在被广泛用于了解生物的结构和功能。一个特别感兴趣的领域是计算蛋白质-配体结合自由能；这些方法正越来越多地用于药物发现。然而，它们受到两个基本问题的限制-用于描述系统中能量和力的底层模型的可靠性，以及模拟算法有效采样系统配置的能力。为了解决这些问题中的第二个，我们开发了我们自己的增强采样方法，并测试了其他人的方法，以改进系统中罕见构象的采样。在这种情况下，我们对非平衡方法越来越感兴趣，即所谓的非平衡候选蒙特卡罗（NCMC），其中对系统进行扰动，并使用与松弛过程相关的功来估计平衡自由能的相关变化。在这个项目中，我们将使用NCMC来模拟与蛋白质配体结合相关的质子化状态的变化。我们将研究蛋白质活性位点内动态质子化状态的影响，以及这如何影响小分子（如潜在候选药物）的结合。该项目的最终目标是在蛋白质-药物结合自由能计算的背景下开发、实施和测试基于ncmc的质子化方法，从而使候选药物的开发速度和准确性更高。

Molecular simulations are now being widely used to understand biological structure and function. An area of particular interest is in calculating protein-ligand binding free energies; these approaches are being increasingly used in the context of pharmaceutical drug discovery. However, they are limited by two fundamental problems - the reliability of the underlying model used to describe the energy and forces in the system, and the ability of the simulation algorithms to sample effectively the configurations of the system.To address the second of these problems, we have developed our own enhanced sampling approaches, and tested those of others, to improve the sampling of rare conformations of the system. In this context, we are becoming increasingly interested in non-equilibrium approaches, so-called non-equilibrium candidate Monte Carlo (NCMC), where perturbations are made to the system, and the work associated with the relaxation process is used to estimate the associated change in equilibrium free energy. In this project we will use NCMC to model changes in protonation states associated with protein-ligand binding. We will examine the effect of dynamic protonation states within a protein's active site and how this affects binding of small molecules such as potential drug candidates. The ultimate goal of this project is to develop, implement and test NCMC-based protonation methodology in the context of protein-drug binding free energy calculations, allowing putative drug candidates to be developed with greater speed and accuracy.