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dc.contributor.authorExternal author(s) only
dc.identifier.citationSumaer Kamboj, Chase Harms, Derek Wright1, Anthony Nash, Lokender Kumar, Judith Klein-Seetharaman, and Susanta K. Sarkar. Quantification of allosteric communications in matrix metalloprotease-1 on alpha-synuclein aggregates and substratedependent virtual screening . bioRxiv preprinten
dc.description.abstractAlpha-synuclein (aSyn) has implications in pathological protein aggregations observed in neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. There are currently no approved prevention and cure for these diseases. In this context, matrix metalloproteases (MMPs) provide an opportunity because MMPs are broad-spectrum proteases and cleave aSyn. Previously, we showed that allosteric communications between the two domains of MMP1 on collagen fibril and fibrin depend on substrates, MMP1 activity, and ligands. However, allosteric communications in MMP1 on aSyn-induced aggregates have not been explored. Here we report quantification of allostery using single molecule measurements of MMP1 dynamics on aSyninduced aggregates by calculating Forster Resonance Energy Transfer (FRET) between two dyes attached to the catalytic and hemopexin domains of MMP1. The two domains of MMP1 prefer open conformations, with the two domains well-separated. These open conformations are inhibited by a single point mutation E219Q of MMP1 and tetracycline, an MMP inhibitor. A two-state Poisson process describes the interdomain dynamics. The best-fit parameters for a Gaussian fit to the distributions of FRET values provide the two states. The ratio of the kinetic rates between the two states comes from the ratio of fitted areas around the two states. The decay rate of an exponential fit to the correlations between FRET values provides the sum of the kinetic rates. Since a crystal structure of aSyn-bound MMP1 is not available, we performed molecular docking of MMP1 with aSyn using ClusPro. We simulated MMP1 dynamics using different docking poses and matched the experimental and simulated interdomain dynamics to determine the most appropriate pose. We performed virtual screening against the potential ligand-binding sites on the appropriate aSyn-MMP1 binding pose and showed that lead molecules differ between free MMP1 and substrate-bound MMP1. In other words, virtual screening needs to take substrates into account for substrate-specific control of MMP1 activity. Molecular understanding of interactions between MMP1 and aSyn-induced aggregates may open up the possibility of degrading pathological aggregates in neurodegeneration by targeting MMPs.en
dc.description.sponsorshipSupported by the NIHRen
dc.subjectAlzheimer's diseaseen
dc.subjectParkinson's Diseaseen
dc.titleQuantification of allosteric communications in matrix metalloprotease-1 on alpha-synuclein aggregates and substratedependent virtual screeningen

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