Transition path sampling study of the reaction catalyzed by purine nucleoside phosphorylase

Suwipa Saen-oon, Vern L. Schramm, Steven D Schwartz

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The Transition Path Sampling (TPS) method is a powerful technique for studying rare events in complex systems, that allows description of reactive events in atomic detail without prior knowledge of reaction coordinates and transition states. We have applied TPS in combination with a hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) method to study the enzyme human purine nucleoside Phosphorylase (hPNP). This enzyme catalyzes the reversible phosphorolysis of 6-oxypurine (deoxy)nucleosides to generate the corresponding purine base and (deoxy)ribose 1-phosphate. Hundreds of reactive trajectories were generated. Analysis of this transition path ensembles provides insight into the detailed mechanistic dynamics of reaction in the enzyme. Our studies have indicated a reaction mechanism involving the cleavage of the N-ribosidic bond to form transition states with substantial ribooxacarbenium ion character, that is then followed by conformational changes in the enzyme and the ribosyl group leading to migration of the anomeric carbon of the ribosyl group toward phosphate to form the product ribose 1-phosphate. This latter process is crucial in PNP, because several strong H-bonds form between active site residues in order to capture and align the phosphate nucleophile. Calculations of the commitment probability along reactive paths demonstrated the presence of a broad energy barrier at the transition state. Analysis of these transition state structures showed that bond-breaking and bond-forming distances are not a good choice for the reaction coordinate, but that the pseudorotational phase of the ribose ring is also a significant variable.

Original languageEnglish (US)
Pages (from-to)1359-1374
Number of pages16
JournalZeitschrift fur Physikalische Chemie
Volume222
Issue number8-9
DOIs
StatePublished - 2008
Externally publishedYes

Fingerprint

Purine-Nucleoside Phosphorylase
purines
nucleosides
sampling
Sampling
ribose
Enzymes
enzymes
phosphates
Phosphates
Nucleophiles
Ribose
Energy barriers
Nucleosides
Large scale systems
Carbon
Trajectories
Ions
nucleophiles
complex systems

Keywords

  • Enzyme catalyzes
  • Purine nucleoside phosphorylase
  • Transition path sampling

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

Transition path sampling study of the reaction catalyzed by purine nucleoside phosphorylase. / Saen-oon, Suwipa; Schramm, Vern L.; Schwartz, Steven D.

In: Zeitschrift fur Physikalische Chemie, Vol. 222, No. 8-9, 2008, p. 1359-1374.

Research output: Contribution to journalArticle

@article{cc49e5c736e4453d893467150ece8465,
title = "Transition path sampling study of the reaction catalyzed by purine nucleoside phosphorylase",
abstract = "The Transition Path Sampling (TPS) method is a powerful technique for studying rare events in complex systems, that allows description of reactive events in atomic detail without prior knowledge of reaction coordinates and transition states. We have applied TPS in combination with a hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) method to study the enzyme human purine nucleoside Phosphorylase (hPNP). This enzyme catalyzes the reversible phosphorolysis of 6-oxypurine (deoxy)nucleosides to generate the corresponding purine base and (deoxy)ribose 1-phosphate. Hundreds of reactive trajectories were generated. Analysis of this transition path ensembles provides insight into the detailed mechanistic dynamics of reaction in the enzyme. Our studies have indicated a reaction mechanism involving the cleavage of the N-ribosidic bond to form transition states with substantial ribooxacarbenium ion character, that is then followed by conformational changes in the enzyme and the ribosyl group leading to migration of the anomeric carbon of the ribosyl group toward phosphate to form the product ribose 1-phosphate. This latter process is crucial in PNP, because several strong H-bonds form between active site residues in order to capture and align the phosphate nucleophile. Calculations of the commitment probability along reactive paths demonstrated the presence of a broad energy barrier at the transition state. Analysis of these transition state structures showed that bond-breaking and bond-forming distances are not a good choice for the reaction coordinate, but that the pseudorotational phase of the ribose ring is also a significant variable.",
keywords = "Enzyme catalyzes, Purine nucleoside phosphorylase, Transition path sampling",
author = "Suwipa Saen-oon and Schramm, {Vern L.} and Schwartz, {Steven D}",
year = "2008",
doi = "10.1524/zpch.2008.5395",
language = "English (US)",
volume = "222",
pages = "1359--1374",
journal = "Zeitschrift fur Physikalische Chemie",
issn = "0942-9352",
publisher = "Oldenbourg Wissenschaftsverlag GmbH",
number = "8-9",

}

TY - JOUR

T1 - Transition path sampling study of the reaction catalyzed by purine nucleoside phosphorylase

AU - Saen-oon, Suwipa

AU - Schramm, Vern L.

AU - Schwartz, Steven D

PY - 2008

Y1 - 2008

N2 - The Transition Path Sampling (TPS) method is a powerful technique for studying rare events in complex systems, that allows description of reactive events in atomic detail without prior knowledge of reaction coordinates and transition states. We have applied TPS in combination with a hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) method to study the enzyme human purine nucleoside Phosphorylase (hPNP). This enzyme catalyzes the reversible phosphorolysis of 6-oxypurine (deoxy)nucleosides to generate the corresponding purine base and (deoxy)ribose 1-phosphate. Hundreds of reactive trajectories were generated. Analysis of this transition path ensembles provides insight into the detailed mechanistic dynamics of reaction in the enzyme. Our studies have indicated a reaction mechanism involving the cleavage of the N-ribosidic bond to form transition states with substantial ribooxacarbenium ion character, that is then followed by conformational changes in the enzyme and the ribosyl group leading to migration of the anomeric carbon of the ribosyl group toward phosphate to form the product ribose 1-phosphate. This latter process is crucial in PNP, because several strong H-bonds form between active site residues in order to capture and align the phosphate nucleophile. Calculations of the commitment probability along reactive paths demonstrated the presence of a broad energy barrier at the transition state. Analysis of these transition state structures showed that bond-breaking and bond-forming distances are not a good choice for the reaction coordinate, but that the pseudorotational phase of the ribose ring is also a significant variable.

AB - The Transition Path Sampling (TPS) method is a powerful technique for studying rare events in complex systems, that allows description of reactive events in atomic detail without prior knowledge of reaction coordinates and transition states. We have applied TPS in combination with a hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) method to study the enzyme human purine nucleoside Phosphorylase (hPNP). This enzyme catalyzes the reversible phosphorolysis of 6-oxypurine (deoxy)nucleosides to generate the corresponding purine base and (deoxy)ribose 1-phosphate. Hundreds of reactive trajectories were generated. Analysis of this transition path ensembles provides insight into the detailed mechanistic dynamics of reaction in the enzyme. Our studies have indicated a reaction mechanism involving the cleavage of the N-ribosidic bond to form transition states with substantial ribooxacarbenium ion character, that is then followed by conformational changes in the enzyme and the ribosyl group leading to migration of the anomeric carbon of the ribosyl group toward phosphate to form the product ribose 1-phosphate. This latter process is crucial in PNP, because several strong H-bonds form between active site residues in order to capture and align the phosphate nucleophile. Calculations of the commitment probability along reactive paths demonstrated the presence of a broad energy barrier at the transition state. Analysis of these transition state structures showed that bond-breaking and bond-forming distances are not a good choice for the reaction coordinate, but that the pseudorotational phase of the ribose ring is also a significant variable.

KW - Enzyme catalyzes

KW - Purine nucleoside phosphorylase

KW - Transition path sampling

UR - http://www.scopus.com/inward/record.url?scp=57349195110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57349195110&partnerID=8YFLogxK

U2 - 10.1524/zpch.2008.5395

DO - 10.1524/zpch.2008.5395

M3 - Article

AN - SCOPUS:57349195110

VL - 222

SP - 1359

EP - 1374

JO - Zeitschrift fur Physikalische Chemie

JF - Zeitschrift fur Physikalische Chemie

SN - 0942-9352

IS - 8-9

ER -