Effects of the Nature of Metal Ion, Protein and Substrate on the Catalytic Center in Matrix Metalloproteinase‐1: Insights from Multilevel MD, QM/MM and QM Studies

Varghese, Ann; Chaturvedi, Shobhit S.; DiCastri, Bella; Mehler, Emerald; Fields, Gregg B.; Karabencheva‐Christova, Tatyana G.

doi:10.1002/cphc.202100680

Cited by 3 publications

(3 citation statements)

References 88 publications

(111 reference statements)

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“…The binding of the THP strand by MMP-1 requires a complex conformational transition between open and closed conformation, involving a change in the coordination state of the catalytic Zn(II). This transition has been demonstrated by both experimental ,, and computational studies. ,, The conformational dynamics of enzymes play a critical role in forming the productive ES complex and, consequently, in the catalytic mechanisms. − Considering the dynamic nature of the multidomain MMP-1·THP complex, it is essential to explore the effect of conformational flexibility , on the catalytic mechanism.…”

Section: Introductionmentioning

confidence: 99%

“…This transition has been demonstrated by both experimental 30,38,39 and computational studies. 31,40,41 The conformational dynamics of enzymes play a critical role in forming the productive ES complex and, consequently, in the catalytic mechanisms. 42−44 Considering the dynamic nature of the multidomain MMP-1•THP complex, it is essential to explore the effect of conformational flexibility 30,39 on the catalytic mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Novel Insights into the Catalytic Mechanism of Collagenolysis by Zn(II)-Dependent Matrix Metalloproteinase-1

Gorantla,

Krishnan,

Waheed

et al. 2024

Biochemistry

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Collagen hydrolysis, catalyzed by Zn(II)-dependent matrix metalloproteinases (MMPs), is a critical physiological process. Despite previous computational investigations into the catalytic mechanisms of MMP-mediated collagenolysis, a significant knowledge gap in understanding remains regarding the influence of conformational sampling and entropic contributions at physiological temperature on enzymatic collagenolysis. In our comprehensive multilevel computational study, employing quantum mechanics/molecular mechanics (QM/MM) metadynamics (MetD) simulations, we aimed to bridge this gap and provide valuable insights into the catalytic mechanism of MMP-1. Specifically, we compared the full enzyme−substrate complex in solution, clusters in solution, and gas-phase to elucidate insights into MMP-1-catalyzed collagenolysis. Our findings reveal significant differences in the catalytic mechanism when considering thermal effects and the dynamic evolution of the system, contrasting with conventional static potential energy surface QM/MM reaction path studies. Notably, we observed a significant stabilization of the critical tetrahedral intermediate, attributed to contributions from conformational flexibility and entropy. Moreover, we found that protonation of the scissile bond nitrogen occurs via proton transfer from a Zn(II)-coordinated hydroxide rather than from a solvent water molecule. Following C−N bond cleavage, the C-terminus remains coordinated to the catalytic Zn(II), while the N-terminus forms a hydrogen bond with a solvent water molecule. Subsequently, the release of the C-terminus is facilitated by the coordination of a water molecule. Our study underscores the pivotal role of protein conformational dynamics at physiological temperature in stabilizing the transition state of the rate-limiting step and key intermediates, compared to the corresponding reaction in solution. These fundamental insights into the mechanism of collagen degradation provide valuable guidance for the development of MMP-1-specific inhibitors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Insights into the Catalytic Mechanism of Collagenolysis by Zn(II)-Dependent Matrix Metalloproteinase-1

Gorantla,

Krishnan,

Waheed

et al. 2024

Biochemistry

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“…In addition to the analysis of ligand−enzyme interactions, MD simulations have been utilized to study the functions of metal ions and MMPs. For example, multilevel computational methods such as MD, quantum mechanics (QM), and QM/MM were applied to examine the effects of the nature of metal ions on the catalytic center in MMP−1 [ 24 ]. The intermolecular interactions and active site conformations of MMP-1 complexed with collagen were studied using combined meta−dynamics, umbrella sampling, and QM/MM calculations [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of Matrix Metalloproteinase 13 and the Analysis of the Specificity Loop and the S1′−Site

Choi

Chung

2023

IJMS

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The specificity loop of Matrix Metalloproteinases (MMPs) is known to regulate recognition of their substrates, and the S1′−site surrounded by the loop is a unique place to address the selectivity of ligands toward each MMP. Molecular dynamics (MD) simulations of apo−MMP−13 and its complex forms with various ligands were conducted to identify the role of the specificity loop for the ligand binding to MMP−13. The MD simulations showed the dual role of T247 as a hydrogen bond donor to the ligand, as well as a contributor to the formation of the van der Waal surface area, with T245 and K249 on the S1′−site. The hydrophobic surface area mediated by T247 blocks the access of water molecules to the S1′−site of MMP−13 and stabilizes the ligand in the site. The F252 residue is flexible in order to search for the optimum location in the S1′−site of the apo−MMP−13, but once a ligand binds to the S1′−site, it can form offset π−π or edge−to−π stacking interactions with the ligand. Lastly, H222 and Y244 provide the offset π−π and π−CH(Cβ) interactions on each side of the phenyl ring of the ligand, and this sandwiched interaction could be critical for the ligand binding to MMP−13.

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Mechanism of the Early Catalytic Events in the Collagenolysis by Matrix Metalloproteinase‐1

et al. 2022

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Metalloproteinase-1 (MMP-1) catalyzed collagen degradation is essential for a wide variety of normal physiological processes, while at the same time contributing to several diseases in humans. Therefore, a comprehensive understanding of this process is of great importance. Although crystallographic and spectroscopic studies provided fundamental information about the structure and function of MMP-1, the precise mechanism of collagen degradation especially considering the complex and flexible structure of the substrate, remains poorly understood. In addition, how the protein environment dynamically reorganizes at the atomic scale into a catalytically active state capable of collagen hydrolysis remains unknown. In this study, we applied experimentally-guided multiscale molecular modeling methods including classical molecular dynamics (MD), welltempered (WT) classical metadynamics (MetD), combined quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM MetD simulations to explore and characterize the early catalytic events of MMP-1 collagenolysis. Importantly the study provided a complete atomic and dynamic description of the transition from the open to the closed form of the MMP-1 * THP complex. Notably, the formation of catalytically active Michaelis complex competent for collagen cleavage was characterized. The study identified the changes in the coordination state of the catalytic zinc(II) associated with the conformational transformation and the formation of catalytically productive ES complex. Our results confirm the essential role of the MMP-1 catalytic domain's α-helices (hA, hB and hC) and the linker region in the transition to the catalytically competent ES complex. Overall, the results provide unique mechanistic insight into the conformational transformations and associated changes in the coordination state of the catalytic zinc(II) that would be important for the design of effective MMP-1 inhibitors.

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Effects of the Nature of Metal Ion, Protein and Substrate on the Catalytic Center in Matrix Metalloproteinase‐1: Insights from Multilevel MD, QM/MM and QM Studies

Cited by 3 publications

References 88 publications

Novel Insights into the Catalytic Mechanism of Collagenolysis by Zn(II)-Dependent Matrix Metalloproteinase-1

Novel Insights into the Catalytic Mechanism of Collagenolysis by Zn(II)-Dependent Matrix Metalloproteinase-1

Molecular Dynamics Simulations of Matrix Metalloproteinase 13 and the Analysis of the Specificity Loop and the S1′−Site

Mechanism of the Early Catalytic Events in the Collagenolysis by Matrix Metalloproteinase‐1

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