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

> **NIH NIH R15** · MICHIGAN TECHNOLOGICAL UNIVERSITY · 2020 · $439,609

## Abstract

PROJECT SUMMARY
The catabolism of collagen (the most abundant protein in human body) is precisely regulated in normal
physiology and a critical physiological process in the extracellular matrix. Abnormal collagen catabolism
is key in the development of pathological conditions such as tumor growth and invasion, arthritis and
fibrosis. However, the mechanism of collagenolisys still remains poorly understood. Thus, understanding
the basic biology and pathology of collagenolysis can help in the development of novel therapeutic agents.
Our preliminary results show that the conformational flexibility in MMP-1 is important and can exercises
impact on its function. Long-term goal of the proposed research is to understand the molecular mechanism
of collagenolysis and to apply this knowledge in developing novel therapeutics by integrated application
of computational and experimental methods. The objective of the proposed research application will be
accomplished by two specific aims: Aim 1 Will define the conformational transition from initially-bound
substrate to MMP-1 to the formation of catalytically productive MMP-1·THP ES complex. The work
hypothesis is that conformational flexibility plays crucial role in the formation of a productive ES complex
and in particular the flexibility of the linker region is a driving force that triggers transition from initially
bound MMP-1·THP complex to catalytically productive ES complex. We suppose that the process
continues with rotation of HPX domain and CAT domain and further unsplitting and insertion of the leading
THP chain in the active site, where it is stabilized by interactions with the active site residues in the CAT
domain. Experimental kinetic studies of the formation of the kinetically productive MMP-1·THP complex
using different clinically important mutations in THPs will be done and will be used for calibration and
validation of the computational predictions. Aim 2 Modeling the reaction mechanism of substrate's L-chain
hydrolysis by MMP-1 and computer-aided design of selective mechanism-based inhibitors of MMP-1. The
hypothesis that MMP-1collagen hydrolysis proceeds via reaction mechanism in four steps: first
nucleophilic attack, then followed by hydrogen bond rearrangement, proton transfer and scissile bond C-N
cleavage will be tested. In addition, we hypothesize that the conformational flexibility exercises sensitive
effects on MMP-1 reaction path. These studies will help us reveal the intimate mechanism of collagen
hydrolysis in MMP-1.

## Key facts

- **NIH application ID:** 9965155
- **Project number:** 1R15GM132873-01A1
- **Recipient organization:** MICHIGAN TECHNOLOGICAL UNIVERSITY
- **Principal Investigator:** Tatyana Karabencheva-Christova
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,609
- **Award type:** 1
- **Project period:** 2020-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965155

## Citation

> US National Institutes of Health, RePORTER application 9965155, Insights in Structure-Function Relationships of Matrix Metalloproteinase-1 from Computational and Experimental Studies (1R15GM132873-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9965155. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*