Development and Application of New Tools for Computational Biophysical Chemistry

计算机模拟已经成为许多化学领域不可或缺的一部分，在这些领域中，分子间的相互作用导致复杂的物理性质，如果没有原子尺度的理解，这些性质很难解释。这在生物系统中尤其如此，因为对蛋白质动态的计算机模拟现在是研究的常规部分。我们研究小组的目标是开发新的模拟方法，使模拟现有工具无法研究的生物化学重要系统成为可能。我们在纪念大学的研究将使用最先进的大西洋卓越计算网络(ACEnet)超级计算机来解决其中两个重要但具有技术挑战性的课题：(1)不可逆酶抑制是一种药物分子通过与其活性部位的氨基酸发生化学反应来停止酶功能的机制。现有的药物，如青霉素和阿司匹林，通过不可逆转的抑制作用发挥作用，并有针对与癌症相关的酶的不可逆转抑制剂的广泛药学研究。现有的计算机程序不能模拟这些酶-药物化学反应，所以我们将使用量子力学/分子力学的混合方法来理解和预测这些假定的抗癌药物的活性。(2)RNA是一种生物大分子，用于将遗传信息从DNA转移到核糖体，在核糖体中为蛋白质合成提供指令。在过去的15年里，人们已经发现了令人兴奋的被称为核糖开关的新RNA结构。这些RNA链折叠成复杂的结构，当它们与它们感觉到的分子结合时，这些结构控制着基因的表达。从计算上探索这些重排的结构和动力学将是非常有价值的，但这些结构很难模拟，因为它们与细胞内的Mg(II)离子形成强烈的静电相互作用，而且它们的结合诱导重排是一个复杂的结构，涉及数千个原子。我们的研究将使用可极化力场和复杂的寻路方法来模拟这些过程。

Computer simulations have become an integral part of many areas of chemistry where intermolecular interactions result in complex physical properties that are difficult to interpret without an atomic-scale understanding. This is especially true in biological systems, as computer simulations of the dynamics of proteins are now a routine part of research. The objective of our research group is to develop new simulation methods that will make it possible to simulate biochemically important systems that cannot be studied with existing tools. Our research at Memorial University will use the state-of-the-art Atlantic Computational Excellence Network (ACEnet) supercomputers to address two of these vital but technically challenging subjects: (1) Irreversible enzyme inhibition is a mechanism by which a drug molecule can stop the function of an enzyme by undergoing a chemical reaction with an amino acid in its active site. Existing drugs such as penicillin and aspirin act through irreversible inhibition and there been extensive pharmaceutical research of irreversible inhibitors that target enzymes relating to cancer. Existing computer programs cannot model these enzyme-drug chemical reactions, so we will use hybrid quantum mechanical/molecular mechanical methods to understand and predict the activity of these putative anti-cancer drugs. (2) RNA is a biological macromolecule that is used to transfer genetic information from DNA to ribosomes, where they provide the instructions for protein synthesis. Over the past 15 years, exciting new RNA structures known as riboswitches have been identified. These RNA strands fold into intricate structures that control gene expression when they are bound to molecules they sense. Exploring the structures and dynamics of these rearrangements computationally would be extremely valuable, however these structures are difficult to simulate as they form strong electrostatic interactions with Mg(II) ions in the cell and their binding-induced rearrangements are a complex, involving thousands of atoms. Our research will employ polarizable force fields in conjunction with sophisticated path-finding methods to simulate these processes.