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了复杂的物理性质，如果没有原子尺度的理解，这些物理性质很难解释。在生物系统中尤其如此，因为计算机模拟蛋白质的动力学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计算卓越网络（ACEnet）超级计算机来解决两个至关重要但技术上具有挑战性的课题：(1)不可逆酶抑制是一种机制，通过这种机制，药物分子可以通过与活性位点的氨基酸发生化学反应来阻止酶的功能。现有的药物如青霉素和阿司匹林是通过不可逆的抑制作用起作用的，针对与癌症有关的酶的不可逆抑制剂的药物研究也很广泛。现有的计算机程序无法模拟这些酶-药物化学反应，因此我们将使用混合量子力学/分子力学方法来了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，核糖体为蛋白质合成提供指令。在过去的15年里，被称为核糖开关的令人兴奋的新RNA结构已经被发现。当这些RNA链与它们感知到的分子结合时，它们折叠成复杂的结构，控制着基因的表达。通过计算来探索这些重排的结构和动力学是非常有价值的，然而这些结构很难模拟，因为它们与细胞中的Mg（II）离子形成强烈的静电相互作用，并且它们的结合诱导重排是一个复杂的过程，涉及数千个原子。我们的研究将采用极化力场结合复杂的寻径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.