Development and Application of New Tools for Computational Biophysical Chemistry

计算机模拟已成为许多化学领域不可或缺的一部分，其中分子间相互作用导致复杂的物理性质，如果没有原子尺度的理解就很难解释。在生物系统中尤其如此，因为蛋白质动力学的计算机模拟现在已成为研究的常规部分。我们研究小组的目标是开发新的模拟方法，使模拟无法用现有工具研究的重要生化系统成为可能。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) 超级计算机来解决其中两个至关重要但在技术上具有挑战性的课题：(1) 不可逆酶抑制是药物分子通过与其活性位点的氨基酸发生化学反应来阻止酶功能的机制。青霉素和阿司匹林等现有药物通过不可逆抑制发挥作用，针对与癌症相关的酶，针对不可逆抑制剂进行了广泛的药物研究。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，并在核糖体中提供蛋白质合成的指令。在过去的 15 年里，令人兴奋的新 RNA 结构（称为核糖开关）已经被发现。当这些 RNA 链与它们所感知的分子结合时，它们会折叠成复杂的结构来控制基因表达。通过计算探索这些重排的结构和动力学将非常有价值，但是这些结构很难模拟，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的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与复杂的寻路方法相结合来模拟这些过程。

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.