METALLOENZYME STRUCTURE/FUNCTION

本研究的目的是发展和应用理论 模拟技术来研究蛋白质的性质和能量学， 底物和蛋白质-抑制剂相互作用， 非催化的溶液相反应和酶催化的 反应. 通过增加我们对现有抑制剂的理解， 以及我们设计新抑制剂的能力将对 改善人类健康。 我们对蛋白质知识的增长 结构和功能将对生物技术产生重大影响， 因为它将允许从头设计新的蛋白质， 增加或更多的选择性催化性能。 为了解决这些问题，我们将采用两种类型的锌 对金属酶进行严格的理论研究。这些是人类 碳酸酐酶（HCA）和基质金属蛋白酶（MMPs）。 特别是，我们将研究HCAII和基质金属蛋白酶溶素-1（S1）， 基质溶解素，HCAII是非常重要的生物医学，因为它的作用， 涉及CO2的过程，并且因为在 青光眼的治疗 S1和基质溶解素在结构上是重要的。 组织和抑制剂的修饰可能用于 关节炎的治疗 此外，相关的MMPs参与疾病 从癌症到牙周病。 因此， S1和matrilysin将揭示相关的MMPs。 为了了解这些酶的结构和功能， 将开发量子力学/分子力学（QM/MM）方法 提高了性能，改善了远程治疗， 相互作用以及确定绝对和相对 束缚自由能 这些新方法提供了超越 因此，我们将获得新的分子水平 对酶的认识。 这些方法将被应用到本研究中 凝聚相反应以及酶/底物相互作用， S1、基质溶解素和HCAII中的金属离子结合、催化和抑制。 这些研究将提供一个分子水平的图片的因素 参与酶的抑制和催化。 我们还将提供我们的 QM/MM计划，以科学界，以便让其他人 使用生物大分子的结构和功能进行探测的能力 工具。

The goal of the proposed research is to develop and apply theoretical simulation techniques to study the nature and energetics of protein- substrate and protein-inhibitor interactions, the mechanism of uncatalyzed solution phase reactions, and enzymatically catalyzed reactions. By increasing our understanding of existing inhibitors as well as our ability to design new inhibitors will have a major impact on improving human health. An increase in our knowledge of protein structure and function will have a major impact on biotechnology, because it will allow for the ab initio design of new proteins with increased or more selective catalytic properties. To address these issues we will subject two classes of zinc metalloenzymes to intense theoretical scrutiny. These are the human carbonic anhydrases (HCAs) and the matrix metalloproteinases (MMPs). In particular, we will look at HCAII and the MMPs stromelysin-1 (S1) and matrilysin, HCAII is of great biomedical importance because of its role in processes involving CO2, and because inhibitors are used in the treatment of glaucoma. S1 and matrilysin are important in structural modification of tissue and inhibitors are potentially useful in the treatment of arthritis. Moreover, related MMPs are involved in diseases ranging from cancer to periodontal disease. Thus, an understanding of S1 and matrilysin will shed light on related MMPs. In order to understand the structure and function of these enzymes we will develop quantum mechanical/molecular mechanical (QM/MM) methods that have improved performance, improved treatment of long-range interactions as well as the ability to determine absolute and relative binding free energies. These new methods offer capabilities beyond traditional methods and, therefore, we will obtain novel molecular-level insights regarding enzymes. These methods will be applied to the study of condensed phase reactions as well as enzyme/substrate interactions, metal ion binding, catalysis and inhibition in S1, matrilysin and HCAII. These studies will provide a molecular-level picture of the factors involved in enzyme inhibition and catalysis. We will also supply our QM/MM programs to the scientific community in order to allow others the ability to probe the structure and function of biomacromolecules using our tools.