METALLOENZYME STRUCTURE/FUNCTION

拟议研究的目标是开发和应用理论 用模拟技术研究蛋白质的性质和能量学- 底物和蛋白质-抑制物相互作用，其机制 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加 结构和功能将对生物技术产生重大影响， 因为它将允许从头开始设计新的蛋白质 增强的或更有选择性的催化性能。 为了解决这些问题，我们将研究两类锌 对金属酶进行了严格的理论审查。这些是人类 碳酸氢酶(HCAs)和基质金属蛋白酶(MMPs)。 特别是，我们将研究HCAII和基质金属蛋白酶基质分解素-1(S1)和 母溶素，HCAII具有重要的生物医学意义，因为它在 涉及二氧化碳的过程，因为抑制剂被用于 青光眼的治疗。S1和Matrilysin在结构上起重要作用 组织和抑制剂的修饰在 治疗关节炎。此外，相关的基质金属蛋白酶与疾病有关。 从癌症到牙周病。因此，对 S1和母溶素将揭示相关的基质金属蛋白。 为了了解这些酶的结构和功能，我们 将开发量子力学/分子力学(QM/MM)方法 改善了性能，改善了远程治疗 相互作用以及确定绝对和相对的能力 结合自由能。这些新方法提供了超越 传统的方法，因此我们将获得新的分子水平 关于酶的见解。这些方法将被应用到研究中 凝聚相反应以及酶/底物相互作用， 金属离子在S1、Matrilysin和HCAII中的结合、催化和抑制。 这些研究将提供这些因素的分子水平图景。 参与酶的抑制和催化。我们还将提供我们的 QM/MM计划给科学界，以便让其他人 探索生物大分子的结构和功能的能力 我们的工具。

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.