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Determination of the structure form of the fourth ligand of zinc in Acutolysin A using combined quantum mechanical and molecular mechanical simulation.

ABSTRACT: Acutolysin A, which is isolated from the snake venom of Agkistrodon acutus, is a member of the SVMPs subfamily of the metzincin family, and it is a snake venom zinc metalloproteinase possessing only one catalytic domain. The catalytic zinc ion, in the active site, is coordinated in a tetrahedral manner with three imidazole nitrogen atoms of histidine and one oxygen atom. It is uncertain whether this oxygen atom is a water molecule or a hydroxide ion just from the three-dimensional X-ray crystal structure. The identity of the fourth ligand of zinc is theoretically determined for the first time by performing both combined quantum mechanical and molecular mechanical (QM/MM) simulation and high-level quantum mechanical calculations. All of the results obtained indicate that the fourth ligand in the active site of the reported X-ray crystal structure is a water molecule rather than a hydroxide anion. On the basis of these theoretical results, we note that the experimental observed pH dependence of the proteolytic and hemorrhagic activity of Acutolysin A can be attributed to the deprotonation of the zinc-bound water to yield a better nucleophile, the hydroxide ion. Structural analyses revealed structural details useful for the understanding of acutolysin catalytic mechanism.

SUBMITTER: Wu EL

PROVIDER: S-EPMC2824792 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Determination of the structure form of the fourth ligand of zinc in Acutolysin A using combined quantum mechanical and molecular mechanical simulation.

Wu Emilia L EL Wong Kin-Yiu KY Zhang Xin X Han Keli K Gao Jiali J

The journal of physical chemistry. B 20090201 8

Acutolysin A, which is isolated from the snake venom of Agkistrodon acutus, is a member of the SVMPs subfamily of the metzincin family, and it is a snake venom zinc metalloproteinase possessing only one catalytic domain. The catalytic zinc ion, in the active site, is coordinated in a tetrahedral manner with three imidazole nitrogen atoms of histidine and one oxygen atom. It is uncertain whether this oxygen atom is a water molecule or a hydroxide ion just from the three-dimensional X-ray crystal ...[more]

PMID: 19191509

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Project description:We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl- ion migration through the transmembrane domain of a prototypical E. coli CLC Cl-/H+ antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl-. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl- traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl- exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl- along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing ? bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl- changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl- and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing ? bonds, missing the stabilizations of the Cl- ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl- transport.

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Determination of the structure form of the fourth ligand of zinc in Acutolysin A using combined quantum mechanical and molecular mechanical simulation.

Publications

Determination of the structure form of the fourth ligand of zinc in Acutolysin A using combined quantum mechanical and molecular mechanical simulation.

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