An electrostatic surface field point approach to the characterisation of biomolecular interactions

分子的大多数重要性质是由它们与其他分子相互作用的方式决定的，这对于几乎所有依赖于选择性分子间相互作用来实现其功能的生物分子来说尤其如此。尽管我们在简单官能团接触水平上对分子间相互作用的理解有所进展，如氢键，疏水相互作用，芳香堆积等，但即使是相对简单的小分子复合物的分子间复合物的结构预测仍然是一项极具挑战性的任务，更不用说蛋白质-蛋白质相互作用了。发展快速准确的计算方法来估计分子间复合物的三维结构和热力学稳定性仍然是一个重大的科学挑战。最先进的是全原子模拟，其中力场仍然太不稳定，无法准确估计自由能，计算量太大，无法用于任何类型的筛选程序，或者使用简单的经验评分函数的对接算法，快速但粗糙。这里提出的研究方案的目标是在中间的某个地方。我们将使用具有良好理论基础且足够稳健的方法来计算准确的自由能，并结合分子结构的简化表示，以允许对大分子和大型化合物库进行快速计算。对接两个分子以预测分子间复合物的结构和稳定性的能力在生物学和医学的所有领域都有明显的应用，其中蛋白质-配体、蛋白质-蛋白质、蛋白质-DNA复合物调节细胞中几乎所有的生物化学。这是一个具有挑战性的目标，目前还没有解决方案的问题有很多方面，例如处理蛋白质中改变相互作用界面性质的大规模环运动，但我们将从更简单的系统开始，逐步解决这些更困难的问题。学术申请人开发了一种小分子的计算方法，该方法基于结合配偶体的静电场的简化表示来准确估计溶液中分子间复合物的稳定性。该行业合作伙伴开发了一种用于小分子的计算方法，该方法基于静电场的不同表示法准确描述了分子间复合物的结构特性。该项目的目的是开发一种新的复合计算方法，该方法采用这两种方法的关键要素，并将它们结合起来，用于准确预测溶液中生物分子复合物的结构和稳定性。这将建立一个新的工具，可以应用于生物学中的广泛问题。发现哪些小分子或大分子可能与特定的靶蛋白结合，对于从基因组中包含的信息到理解生物体的功能生物化学具有巨大的价值。这里概述的方法为提高我们在这一努力中取得成功的机会提供了一个有希望的战略。

Most of the important properties of molecules are determined by the way they interact with other molecules, and this is particularly true of biomolecules that almost all rely on selective intermolecular interactions for their function. Despite advances in our understanding of intermolecular interactions at the level of simple functional group contacts, such as H-bonding, hydrophobic interaction, aromatic stacking etc, it is still an extremely challenging task to predict the structure of intermolecular complexes of even relatively simple small molecule complexes, let alone protein-protein interactions. The development of fast and accurate methods for computationally estimating the three-dimensional structures and thermodynamic stability of intermolecular complexes remains a major scientific challenge. The state-of-the-art is either all atom simulations, where the force-fields are still too unstable to allow accurate estimation of free energies and the calculations are too large to use in any kind of screening programme, or docking algorithms that use simple empirical scoring functions, which are fast but crude. The research programme proposed here aims somewhere in the middle. We will use methods that have a sound theoretical basis and are sufficiently robust to calculate accurate free energies, combined with a stripped down representation of molecular structure to allow rapid calculations on macromolecules and large compounds libraries. The ability to dock two molecules to predict the structure and stability of the intermolecular complex has obvious applications in all areas of biology and medicine, where protein-ligand, protein-protein, protein-DNA complexes regulate almost all biochemistry in the cell. This is a challenging target and there are many aspects to the problem for which no current solutions exist, eg handling of large scale loop movements in proteins that alter the nature of interaction interfaces, but we will start with simpler systems and gradually work towards these more difficult problems. The academic applicant has developed a computational approach for small molecules that accurately estimates the stability of intermolecular complexes in solution based on a reduced representation of the electrostatic fields of binding partners. The industry partner has developed a computational approach for small molecules that accurately describes the structural properties of intermolecular complexes based on a different representation of the electrostatic field. The aim of this project is to develop a new composite computational method that takes key elements of these two approaches and combines them for the accurate prediction of the structure and stability of biomolecular complexes in solution. This will establish a new tool that could be applied to a wide range of problems in biology. Discovering what small molecules or macromolecules are likely to bind to a specific target protein would be of immense value in progressing from the information contained in genomes to an understanding of the functional biochemistry of living organisms. The approach outlined here provides a promising strategy for improving our chances of success in this endeavour.