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

Michigan Technological University, Houghton MI

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Abstract

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.