This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent proteolytic enzymes that degrade and remodel all the major components of the extracellular matrix, the space between the cells. Playing such a broad physiological role the MMPs have been implicated in a host of diseases including cancer, arthritis, and cardiovascular disease. However, over the last two decades much effort and little reward have been realized toward their control. The catalytic site in all MMPs consists of a zinc ion coordinated to side chain nitrogen atoms of 3 histidine amino acids(residues). The fourth coordination site is occupied by a water molecule in the active form of the enzyme producing the [(His)3Zn(II)-L] (L=OH2) catalytic center. This water molecule replaces a cysteine sulfur atom, which is bound in the inactive enzyme, or is replaced by the zinc binding group of an inhibitor, a molecule that stops catalysis. Known critical proton transfer steps occur in the MMP mechanism of catalytic action and activation steps, and are also thought to occur during inhibition. This proposal involves theoretical calculations of the MMP active site, with the hypothesis that structural changes about the zinc ion have a significant impact on the energetics of these proton transfer processes, as outlined: To examine the geometric influences on protonation state of the MMPs active site, hybrid quantum mechanical/semi-empirical calculations will be performed on large MMP active site models. The model will encompass the entire HExGHxxGxxH sequence of conserved residues of the catalytic domain. The HExGHxxGxxH sequence is the signature zinc-binding motif of all MMPs, with the catalytic zinc ion coordinated to these 3 histidine (H) residues. The zinc ion, the three coordinated histidines, the glutamate (E in the sequence), and the fourth zinc coordinated ligand (L = OH2 or SHCH3), will be treated using density functional theory or MP2 theory, while the rest of the sequence is treated using the semi-empirical PM3 method. Zinc geometry influences on the protonation state of the zinc bound ligands will be analyzed, and key interactions will be identified detailing the molecular basis for the zinc geometry versus protonation state relationship. The hybrid calculations will utilize the ONIOM technique employed in the Gaussian 03 software and the computations will be carried out by myself and 1 or 2 undergraduate researchers.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR006009-20
Application #
8171869
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (40))
Project Start
2010-08-01
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2013-07-31
Support Year
20
Fiscal Year
2010
Total Cost
$1,091
Indirect Cost
Name
Carnegie-Mellon University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Simakov, Nikolay A; Kurnikova, Maria G (2018) Membrane Position Dependency of the pKa and Conductivity of the Protein Ion Channel. J Membr Biol 251:393-404
Yonkunas, Michael; Buddhadev, Maiti; Flores Canales, Jose C et al. (2017) Configurational Preference of the Glutamate Receptor Ligand Binding Domain Dimers. Biophys J 112:2291-2300
Hwang, Wonmuk; Lang, Matthew J; Karplus, Martin (2017) Kinesin motility is driven by subdomain dynamics. Elife 6:
Earley, Lauriel F; Powers, John M; Adachi, Kei et al. (2017) Adeno-associated Virus (AAV) Assembly-Activating Protein Is Not an Essential Requirement for Capsid Assembly of AAV Serotypes 4, 5, and 11. J Virol 91:
Subramanian, Sandeep; Chaparala, Srilakshmi; Avali, Viji et al. (2016) A pilot study on the prevalence of DNA palindromes in breast cancer genomes. BMC Med Genomics 9:73
Ramakrishnan, N; Tourdot, Richard W; Radhakrishnan, Ravi (2016) Thermodynamic free energy methods to investigate shape transitions in bilayer membranes. Int J Adv Eng Sci Appl Math 8:88-100
Zhang, Yimeng; Li, Xiong; Samonds, Jason M et al. (2016) Relating functional connectivity in V1 neural circuits and 3D natural scenes using Boltzmann machines. Vision Res 120:121-31
Lee, Wei-Chung Allen; Bonin, Vincent; Reed, Michael et al. (2016) Anatomy and function of an excitatory network in the visual cortex. Nature 532:370-4
Murty, Vishnu P; Calabro, Finnegan; Luna, Beatriz (2016) The role of experience in adolescent cognitive development: Integration of executive, memory, and mesolimbic systems. Neurosci Biobehav Rev 70:46-58
Jurkowitz, Marianne S; Patel, Aalapi; Wu, Lai-Chu et al. (2015) The YhhN protein of Legionella pneumophila is a Lysoplasmalogenase. Biochim Biophys Acta 1848:742-51

Showing the most recent 10 out of 292 publications