Insights into Structure-Function Relationships of Matrix Metalloproteinase-1 from Computational and Experimental Studies

从计算和实验研究中洞察基质金属蛋白酶-1 的结构-功能关系

• 批准号: 10730598
• 负责人: Tatyana Karabencheva-Christova
• 金额: $ 42.7万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730598
• 关键词: Active Sites; Adopted; Basic Science; Biochemical; Biological Process; Biomedical Research; Calibration; Catabolism; Chemicals; Collagen; Complex; Computing Methodologies; Development; Disease; Elements; Enzymes; Foundations; Free Energy; Future; Goals; Hydrolysis; Interstitial Collagenase; Investigation; Kinetics; Knowledge; Learning; Link; Malignant neoplasm of lung; Maps; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurement; Methods; Mission; Modeling; Molecular; Molecular Conformation; Mutation; National Institute of General Medical Sciences; Pathologic; Peptides; Prevention; Process; Quantum Mechanics; Reaction; Research; Structure; Structure-Activity Relationship; T Chain; Therapeutic; Therapeutic Agents; Training; Tumor Cell Invasion; Validation; analog; breast cancer progression; computer studies; design; disease diagnosis; experimental study; inhibitor; insight; leukemia; melanoma; molecular mechanics; molecular modeling; mutant; novel strategies; novel therapeutics; restoration; simulation; student training; training opportunity; triple helix; tumor growth; undergraduate student

PROJECT SUMMARY Changes in the activity of collagenolytic matrix metalloproteinase-1 (MMP-1) have been linked to the progression of breast and lung cancer, leukemia, and melanoma. A complete understanding of MMP-1’s structure, mechanism, and function will aid the development of specific inhibitors of MMP-1 for treating diseases that have significant societal impact. The overarching goal of the proposed research is to provide the missing knowledge about conformational and mechanistic aspects of structure-function relationships in MMP-1 and to explain the effects of disease-related mutations in triple-helical peptide (THP) collagen models and MMP-1 at an atomistic level. The central hypothesis, supported by preliminary studies, is that MMP-1 collagenolysis critically relies on complex conformational changes that involve the enzyme's main structural elements and the THP. We further hypothesize that long-range correlated interactions with remote residues can control the catalytic mechanism of MMP-1. The goal of the proposed research application will be accomplished by two specific aims: Aim 1: What is the mechanism of product release after collagenolysis of the THP’s leading (L) chain? The study will determine the structural changes and energetics associated with the release of the product of the collagenolysis of the L chain of THP. Aim 2: What is the catalytic mechanism of collagenolysis of THP’s middle (M) and trailing (T) chains? The goal of Aim 2 is to model the catalytic mechanism of THP’s middle (M) and trailing (T) chains collagenolysis by means of combined quantum mechanics/molecular mechanics (QM/MM) methods and to validate the model using experimental measurements. The research adopts a novel approach by integrating state-of-the-art multilevel molecular modeling approaches in synergistic combination with experimental methods., thus offering unique opportunities for training undergraduate students in promising directions of biomedical research.

项目总结 胶原酶活性变化与基质金属蛋白酶-1(MMP1)活性改变有关 乳腺癌、肺癌、白血病和黑色素瘤的进展。完全了解 研究基质金属蛋白酶-1‘S的结构、机制和功能将有助于开发特异性的血管内皮细胞生长抑制因子 基质金属蛋白酶-1用于治疗具有重大社会影响的疾病。的首要目标是 提出的研究是提供关于构象和机制的缺失的知识 基质金属蛋白酶-1的结构-功能关系及对疾病相关效应的解释 三螺旋多肽(THP)胶原模型和基质金属蛋白酶-1在原子水平上的突变。这个 得到初步研究支持的中心假说是，基质金属蛋白酶-1的胶原酶分解关键依赖于 关于复杂的构象变化涉及酶的主要结构元素和 THP。我们进一步假设，与远程残基的远程相关相互作用可以 控制基质金属蛋白酶-1的催化机制。拟议的研究申请的目标将是 通过两个具体目标实现：目标1：产品发布后的机制是什么 THP的主链(L)的胶原酶溶解？这项研究将确定结构性变化 和与L链胶原酶分解产物的释放有关的能量学 THP。目的2：THP中间(M)和拖尾胶原酶分解的催化机制是什么 (T)链条？目标2的目标是模拟THP的中间(M)和拖尾的催化机理 (T)链胶原蛋白的量子力学/分子力学联合研究 (QM/MM)方法，并通过实验测量来验证模型。这项研究 采用了一种新的方法，集成了最先进的多水平分子建模方法 与实验方法协同结合，从而为 培养本科生在生物医学研究的有前途的方向。