Modelling variable protonation states in protein-ligand systems

模拟蛋白质配体系统中的可变质子化状态

• 批准号: 2446832
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2446832
• 关键词: Modelling; variable; protonation; states; protein

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.

分子模拟现在被广泛用于了解生物结构和功能。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被用于药物发现的背景下。然而，它们受到两个基本问题的限制--用于描述系统中的能量和力的底层模型的可靠性，以及模拟算法对系统构型进行有效采样的能力。为了解决第二个问题，我们开发了自己的增强采样方法，并测试了其他方法，以提高对系统罕见构象的采样。在这种背景下，我们对非平衡方法，即所谓的非平衡候选蒙特卡罗(NCMC)越来越感兴趣，在这种方法中，对系统进行微扰，与松弛过程相关的功被用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部位内动态质子化状态的影响，以及这如何影响小分子的结合，例如潜在的候选药物。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，从而以更快的速度和更准确的速度开发假定的候选药物。