Computational Studies of Aqueous Solvation of Proteins

蛋白质水溶剂化的计算研究

• 批准号: 1464766
• 负责人: Toshiko Ichiye
• 金额: $ 45万
• 依托单位: Georgetown University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1464766&HistoricalAwards=false
• 关键词: Computational; Studies; Aqueous; Solvation; Proteins

With this award, the Chemical Theory, Models and Computational Methods program in the Division of Chemistry (CHE) and the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences (MCB) are supporting Toshiko Ichiye of Georgetown University for computational studies of the aqueous solvation of proteins. Although water is the most common liquid on this planet, the molecular bases of its unique properties as a liquid and a solvent that make it critical for life are still unclear. While it is generally accepted that the tetrahedral network of hydrogen bonds is essential, the critical features in a water molecule that lead to hydrogen bonds are just beginning to be understood. Given its unique liquid properties, this is not surprising but it makes modeling water in computer simulations difficult. However, since computer simulations using atomistic representations of biological macromolecules in aqueous solutions have become critical in understanding many biological problems, accurate representations of both the bio-macromolecule and its surrounding water are essential. Therefore, identifying these features and determining the best ways to model them will impact the understanding of structure and function of biological molecules, including proteins, nucleic acids, lipid membranes, and their assemblies. Moreover, computer simulations are being used to understand scientific questions in many areas of chemistry and physics, and given the importance of water as a liquid and solvent; these studies will have a broad impact on other fields. In addition, the implementation into a commonly used biomolecular simulation package means that our methods will be widely available.The study is to develop a molecular understanding of water and aqueous solutions and, based on this, to develop new atomistic models for water and proteins in computer simulations. The approach of Ichiye and her research group is to understand water is by determining the minimal molecular features necessary to model its unique properties in molecular dynamics computer simulations, which must be its essential molecular features. This approach has been used to understand water as a pure liquid; now the anomalous properties of aqueous ionic solutions are being studied. This approach to modeling water is also unique in that molecular multipoles centered only on the oxygen are used to represent the charge distribution due to both the nuclei and the electron density, which is especially important for reproducing the properties of water. Molecular multipoles are superior to adding dummy sites representing electron density in a site model, because electrons are not point particles. Thus, these models are more accurate than four- and five-site water models and at least two times computationally faster than even three-site models. These ideas will now be used to develop an accurate but efficient force field for ions, co-solutes, and eventually proteins. Molecular multipoles will also be used: multipoles will be placed on the heavy atoms somewhat like the traditional united atom approach, except that the electrostatics of both the hydrogens and electron density will be treated via the multipoles. The aim is to develop a force field that is more accurate than the most commonly used non-polarizable force fields for biomolecules and that is also two to three times faster computationally.

获得该奖项后，化学系(CHE)的化学理论、模型和计算方法项目(CHE)以及分子和细胞生物科学系(MCB)的分子生物物理组支持乔治敦大学的Toshiko Ichiye进行蛋白质水溶液溶剂化的计算研究。尽管水是地球上最常见的液体，但它作为液体和溶剂的独特性质的分子基础仍然不清楚，这些特性使它对生命至关重要。虽然人们普遍认为氢键的四面体网络是必不可少的，但人们对水分子中导致氢键的关键特征才刚刚开始了解。考虑到其独特的液体性质，这并不令人惊讶，但这使得在计算机模拟中对水进行建模变得困难。然而，由于使用水溶液中生物大分子的原子表示的计算机模拟已经成为理解许多生物学问题的关键，所以准确地表示生物大分子及其周围的水是必不可少的。因此，识别这些特征并确定对它们进行建模的最佳方法将影响对生物分子的结构和功能的理解，包括蛋白质、核酸、脂膜及其组装。此外，由于水作为液体和溶剂的重要性，计算机模拟正被用于理解许多化学和物理领域的科学问题；这些研究将对其他领域产生广泛影响。此外，在一个常用的生物分子模拟程序包中的实现意味着我们的方法将被广泛使用。本研究旨在发展对水和水溶液的分子理解，并在此基础上开发计算机模拟中水和蛋白质的新的原子模型。Ichiye和她的研究小组的方法是通过确定在分子动力学计算机模拟中模拟水的独特性质所需的最小分子特征来理解水，这肯定是它的基本分子特征。这种方法已经被用来理解水是一种纯液体；现在正在研究离子水溶液的反常性质。这种模拟水的方法也是独特的，因为只以氧为中心的分子多极被用来表示由于原子核和电子密度而引起的电荷分布，这对于再现水的性质特别重要。分子多极优于在位置模型中添加代表电子密度的虚拟位置，因为电子不是点粒子。因此，这些模型比四个和五个站点的水模型更准确，甚至比三个站点的模型至少快两倍的计算速度。这些想法现在将被用来为离子、共溶质和最终的蛋白质开发一个准确而有效的力场。分子多极也将被使用：多极将被放置在重原子上，有点像传统的联合原子方法，除了氢原子和电子密度的静电将通过多极来处理。其目的是开发一种比生物分子最常用的不可极化力场更精确的力场，并且在计算上也快两到三倍。