Quantum mechanical/molecular mechanical study of the HDV ribozyme: Impact of the catalytic metal ion on the mechanism

Abir Ganguly, Philip C. Bevilacqua, Sharon Hammes-Schiffer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

A recent crystal structure of the precleaved HDV ribozyme along with biochemical data support a mechanism for phosphodiester bond self-cleavage in which C75 acts as a general acid and bound Mg2+ ion acts as a Lewis acid. Herein this precleaved crystal structure is used as the basis for quantum mechanical/molecular mechanical calculations. These calculations indicate that the self-cleavage reaction is concerted with a phosphorane-like transition state when a divalent ion, Mg2+ or Ca2+, is bound at the catalytic site but is sequential with a phosphorane intermediate when a monovalent ion, such as Na+, is at this site. Electrostatic potential calculations suggest that the divalent metal ion at the catalytic site lowers the pKa of C75, leading to the concerted mechanism in which the proton is partially transferred to the leaving group in the phosphorane-like transition state. These observations are consistent with experimental data, including pKa measurements, reaction kinetics, and proton inventories with divalent and monovalent ions.

Original languageEnglish (US)
Pages (from-to)2906-2911
Number of pages6
JournalJournal of Physical Chemistry Letters
Volume2
Issue number22
DOIs
StatePublished - Nov 17 2011

Fingerprint

Catalytic RNA
Phosphoranes
Metal ions
metal ions
Ions
Protons
cleavage
ions
Crystal structure
Lewis Acids
acids
crystal structure
protons
Acids
Reaction kinetics
Electrostatics
reaction kinetics
electrostatics

All Science Journal Classification (ASJC) codes

  • Materials Science(all)
  • Physical and Theoretical Chemistry

Cite this

@article{51ba8b0461f94982b986a4bfde2ca369,
title = "Quantum mechanical/molecular mechanical study of the HDV ribozyme: Impact of the catalytic metal ion on the mechanism",
abstract = "A recent crystal structure of the precleaved HDV ribozyme along with biochemical data support a mechanism for phosphodiester bond self-cleavage in which C75 acts as a general acid and bound Mg2+ ion acts as a Lewis acid. Herein this precleaved crystal structure is used as the basis for quantum mechanical/molecular mechanical calculations. These calculations indicate that the self-cleavage reaction is concerted with a phosphorane-like transition state when a divalent ion, Mg2+ or Ca2+, is bound at the catalytic site but is sequential with a phosphorane intermediate when a monovalent ion, such as Na+, is at this site. Electrostatic potential calculations suggest that the divalent metal ion at the catalytic site lowers the pKa of C75, leading to the concerted mechanism in which the proton is partially transferred to the leaving group in the phosphorane-like transition state. These observations are consistent with experimental data, including pKa measurements, reaction kinetics, and proton inventories with divalent and monovalent ions.",
author = "Abir Ganguly and Bevilacqua, {Philip C.} and Sharon Hammes-Schiffer",
year = "2011",
month = "11",
day = "17",
doi = "10.1021/jz2013215",
language = "English (US)",
volume = "2",
pages = "2906--2911",
journal = "Journal of Physical Chemistry Letters",
issn = "1948-7185",
publisher = "American Chemical Society",
number = "22",

}

Quantum mechanical/molecular mechanical study of the HDV ribozyme : Impact of the catalytic metal ion on the mechanism. / Ganguly, Abir; Bevilacqua, Philip C.; Hammes-Schiffer, Sharon.

In: Journal of Physical Chemistry Letters, Vol. 2, No. 22, 17.11.2011, p. 2906-2911.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Quantum mechanical/molecular mechanical study of the HDV ribozyme

T2 - Impact of the catalytic metal ion on the mechanism

AU - Ganguly, Abir

AU - Bevilacqua, Philip C.

AU - Hammes-Schiffer, Sharon

PY - 2011/11/17

Y1 - 2011/11/17

N2 - A recent crystal structure of the precleaved HDV ribozyme along with biochemical data support a mechanism for phosphodiester bond self-cleavage in which C75 acts as a general acid and bound Mg2+ ion acts as a Lewis acid. Herein this precleaved crystal structure is used as the basis for quantum mechanical/molecular mechanical calculations. These calculations indicate that the self-cleavage reaction is concerted with a phosphorane-like transition state when a divalent ion, Mg2+ or Ca2+, is bound at the catalytic site but is sequential with a phosphorane intermediate when a monovalent ion, such as Na+, is at this site. Electrostatic potential calculations suggest that the divalent metal ion at the catalytic site lowers the pKa of C75, leading to the concerted mechanism in which the proton is partially transferred to the leaving group in the phosphorane-like transition state. These observations are consistent with experimental data, including pKa measurements, reaction kinetics, and proton inventories with divalent and monovalent ions.

AB - A recent crystal structure of the precleaved HDV ribozyme along with biochemical data support a mechanism for phosphodiester bond self-cleavage in which C75 acts as a general acid and bound Mg2+ ion acts as a Lewis acid. Herein this precleaved crystal structure is used as the basis for quantum mechanical/molecular mechanical calculations. These calculations indicate that the self-cleavage reaction is concerted with a phosphorane-like transition state when a divalent ion, Mg2+ or Ca2+, is bound at the catalytic site but is sequential with a phosphorane intermediate when a monovalent ion, such as Na+, is at this site. Electrostatic potential calculations suggest that the divalent metal ion at the catalytic site lowers the pKa of C75, leading to the concerted mechanism in which the proton is partially transferred to the leaving group in the phosphorane-like transition state. These observations are consistent with experimental data, including pKa measurements, reaction kinetics, and proton inventories with divalent and monovalent ions.

UR - http://www.scopus.com/inward/record.url?scp=81755171288&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81755171288&partnerID=8YFLogxK

U2 - 10.1021/jz2013215

DO - 10.1021/jz2013215

M3 - Article

C2 - 22163069

AN - SCOPUS:81755171288

VL - 2

SP - 2906

EP - 2911

JO - Journal of Physical Chemistry Letters

JF - Journal of Physical Chemistry Letters

SN - 1948-7185

IS - 22

ER -