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.

项目摘要 胶原溶解性基质金属蛋白酶-1（MMP-1）活性的变化与 乳腺癌、肺癌、白血病和黑色素瘤的进展。的完整理解 MMP-1的结构，机制和功能的研究将有助于开发特异性抑制剂， MMP-1用于治疗具有显著社会影响的疾病。的首要目标 建议的研究是提供关于构象和机理的缺失知识， MMP-1的结构-功能关系方面，并解释疾病相关的影响， 三螺旋肽（THP）胶原模型和MMP-1在原子水平上的突变。的 初步研究支持的中心假设是MMP-1胶原溶解主要依赖于 复杂的构象变化，涉及酶的主要结构元件和 THP。我们进一步假设，远程相关的相互作用与远程残基， 控制MMP-1的催化机制。拟议研究申请的目标将是 通过两个具体目标来实现：目标1：产品发布后的机制是什么？ THP的前导（L）链的胶原溶解？这项研究将确定结构变化 以及与L链的胶原蛋白溶解产物的释放相关的能量学。 THP。目的2：THP中、尾部胶原酶催化降解的机制是什么 (T)锁链？目标2的目标是模拟THP中间（M）和拖尾的催化机理 (T)量子力学/分子力学相结合的链胶原溶解 (QM/MM）方法，并使用实验测量验证模型。研究 采用了一种新的方法，通过整合最先进的多级分子建模方法， 与实验方法协同组合，从而提供了独特的机会， 在有前途的生物医学研究方向上培养本科生。