QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the
Feasibility of Multiple Competing Reaction Mechanisms

J 2011

QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms

MLÝNSKÝ, Vojtěch, Pavel BANÁŠ, Nils G. WALTER, Jiří ŠPONER, Michal OTYEPKA et. al.

Basic information

Original name

QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms

Authors

MLÝNSKÝ, Vojtěch (203 Czech Republic), Pavel BANÁŠ (203 Czech Republic), Nils G. WALTER (276 Germany), Jiří ŠPONER (203 Czech Republic, guarantor, belonging to the institution) and Michal OTYEPKA (203 Czech Republic)

Edition

JOURNAL OF PHYSICAL CHEMISTRY B, Washington, American Chemical Society, 2011, 1520-6106

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10403 Physical chemistry

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.696

RIV identification code

RIV/00216224:14740/11:00050558

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1021/jp206963g

UT WoS

000297195400014

Keywords in English

TRANSITION-STATE STABILIZATION; BASE-PHOSPHATE INTERACTIONS; DENSITY-FUNCTIONAL THEORY; MATRIX PROPAGATION ADMP; DELTA-VIRUS RIBOZYME; ACTIVE-SITE ADENINE; MOLECULAR-DYNAMICS; STRUCTURAL DYNAMICS; ENZYMATIC-REACTIONS; PHOSPHORYL TRANSFER

Abstract

V originále

The hairpin ribozyme is a prominent member of small ribozymes since it does not require metal ions to achieve catalysis. Guanine 8 (G8) and adenine 38 (A38) have been identified as key participants in self-cleavage and -ligation. We have carried out hybrid quantum-mechanical/molecular mechanical (QM/MM) calculations to evaluate the energy along several putative reaction pathways. The error of our DFT description of the QM region was tested and shown to be similar to 1 kcal/mol. We find that self-cleavage of the hairpin ribozyme may follow several competing microscopic reaction mechanisms, all with calculated activation barriers in good agreement with those from experiment (20-21 kcal/mol). The initial nucleophilic attack of the A-1(2'-OH) group on the scissile phosphate is predicted to be rate-limiting in all these mechanisms. An unprotonated G8(-) (together with A38H(+)) yields a feasible activation barrier (20.4 kcal/mol). Proton transfer to a nonbridging phosphate oxygen also leads to feasible reaction pathways. Finally, our calculations consider thio-substitutions of one or both nonbridging oxygens of the scissile phosphate and predict that they have only a negligible effect on the reaction barrier, as observed experimentally.

Links

ED1.1.00/02.0068, research and development project

Name: CEITEC - central european institute of technology

GD203/09/H046, research and development project

Name: Biochemie na rozcestí mezi in silico a in vitro

Investor: Czech Science Foundation

LC06030, research and development project

Name: Biomolekulární centrum

Investor: Ministry of Education, Youth and Sports of the CR, Biomolecular centre

Citovat

MLÝNSKÝ, Vojtěch, Pavel BANÁŠ, Nils G. WALTER, Jiří ŠPONER and Michal OTYEPKA. QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms. JOURNAL OF PHYSICAL CHEMISTRY B. Washington: American Chemical Society, 2011, vol. 115, No 47, p. 13911-13924. ISSN 1520-6106. Available from: https://dx.doi.org/10.1021/jp206963g.

@article{975015,
   author = {Mlýnský, Vojtěch and Banáš, Pavel and Walter, Nils G. and Šponer, Jiří and Otyepka, Michal},
   article_location = {Washington},
   article_number = {47},
   doi = {http://dx.doi.org/10.1021/jp206963g},
   keywords = {TRANSITION-STATE STABILIZATION; BASE-PHOSPHATE INTERACTIONS; DENSITY-FUNCTIONAL THEORY; MATRIX PROPAGATION ADMP; DELTA-VIRUS RIBOZYME; ACTIVE-SITE ADENINE; MOLECULAR-DYNAMICS; STRUCTURAL DYNAMICS; ENZYMATIC-REACTIONS; PHOSPHORYL TRANSFER},
   language = {eng},
   issn = {1520-6106},
   journal = {JOURNAL OF PHYSICAL CHEMISTRY B},
   title = {QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms},
   url = {http://pubs.acs.org/doi/abs/10.1021/jp206963g},
   volume = {115},
   year = {2011}
}

TY  - JOUR
ID  - 975015
AU  - Mlýnský, Vojtěch - Banáš, Pavel - Walter, Nils G. - Šponer, Jiří - Otyepka, Michal
PY  - 2011
TI  - QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms
JF  - JOURNAL OF PHYSICAL CHEMISTRY B
VL  - 115
IS  - 47
SP  - 13911-13924
EP  - 13911-13924
PB  - American Chemical Society
SN  - 15206106
KW  - TRANSITION-STATE STABILIZATION
KW  - BASE-PHOSPHATE INTERACTIONS
KW  - DENSITY-FUNCTIONAL THEORY
KW  - MATRIX PROPAGATION ADMP
KW  - DELTA-VIRUS RIBOZYME
KW  - ACTIVE-SITE ADENINE
KW  - MOLECULAR-DYNAMICS
KW  - STRUCTURAL DYNAMICS
KW  - ENZYMATIC-REACTIONS
KW  - PHOSPHORYL TRANSFER
UR  - http://pubs.acs.org/doi/abs/10.1021/jp206963g
L2  - http://pubs.acs.org/doi/abs/10.1021/jp206963g
N2  - The hairpin ribozyme is a prominent member of small ribozymes since it does not require metal ions to achieve catalysis. Guanine 8 (G8) and adenine 38 (A38) have been identified as key participants in self-cleavage and -ligation. We have carried out hybrid quantum-mechanical/molecular mechanical (QM/MM) calculations to evaluate the energy along several putative reaction pathways. The error of our DFT description of the QM region was tested and shown to be similar to 1 kcal/mol. We find that self-cleavage of the hairpin ribozyme may follow several competing microscopic reaction mechanisms, all with calculated activation barriers in good agreement with those from experiment (20-21 kcal/mol). The initial nucleophilic attack of the A-1(2'-OH) group on the scissile phosphate is predicted to be rate-limiting in all these mechanisms. An unprotonated G8(-) (together with A38H(+)) yields a feasible activation barrier (20.4 kcal/mol). Proton transfer to a nonbridging phosphate oxygen also leads to feasible reaction pathways. Finally, our calculations consider thio-substitutions of one or both nonbridging oxygens of the scissile phosphate and predict that they have only a negligible effect on the reaction barrier, as observed experimentally.
ER  -

MLÝNSKÝ, Vojtěch, Pavel BANÁŠ, Nils G. WALTER, Jiří ŠPONER and Michal OTYEPKA. QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms. \textit{JOURNAL OF PHYSICAL CHEMISTRY B}. Washington: American Chemical Society, 2011, vol.~115, No~47, p.~13911-13924. ISSN~1520-6106. Available from: https://dx.doi.org/10.1021/jp206963g.

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