Effective Computational Strategies for Determining Structures of Carcinogen-Damaged DNA

S. Broyde, B. E. Hingerty

Research output: Contribution to journalArticle

Abstract

To determine three-dimensional conformations of DNA damaged by environmental chemical carcinogens, effective molecular mechanics search techniques have been developed to deal with the large system sizes and computational demands. First, extensive surveys of the potential energy surface are carried out by energy minimization. These search strategies rely on (1) using the reduced variable domain of torsion-angle (rather than Cartesian) space, (2) building larger units (about 12 base pairs) on the basis of structures of small modified subunits, and (3) employing penalty functions to search for selected hydrogen bonding patterns and to incorporate interproton distance bounds when available from experimental high-resolution nuclear magnetic resonance (NMR) studies. Second, molecular dynamics simulations with solvent can subsequently be employed to probe conformational features in the presence of polymerase enzyme responsible for DNA replication, using structures computed in the energy minimization searches as initial coordinates. A key structure-function relationship involving mirror-image molecules with very differing experimentally determined tumorigenic potencies has been deduced: the members of the pairs align oppositely when bound to DNA, making it likely that their treatment by replication and repair enzymes differ. This opposite orientation phenomenon, first predicted computationally (Singhet al., 1991), has been observed in experimental high-resolution NMR studies combined with our molecular mechanics computations in a number of different examples and has recently been confirmed experimentally in other laboratories as well (reviewed in Geacintovet al., 1997). Elucidation of this conformational feature has paved the way to uncovering the structural origin underlying very different biological outcomes stemming from chemically identical but mirror-image molecules.

Original languageEnglish (US)
Pages (from-to)313-332
Number of pages20
JournalJournal of Computational Physics
Volume151
Issue number1
DOIs
StatePublished - May 1 1999

Fingerprint

carcinogens
Carcinogens
Molecular mechanics
DNA
deoxyribonucleic acid
enzymes
Mirrors
Enzymes
Nuclear magnetic resonance
penalty function
mirrors
Potential energy surfaces
nuclear magnetic resonance
Molecules
optimization
high resolution
Torsional stress
torsion
Conformations
Molecular dynamics

Keywords

  • Carcinogen-DNA structures
  • Molecular dynamics
  • Molecular mechanics

ASJC Scopus subject areas

  • Computer Science Applications
  • Physics and Astronomy(all)

Cite this

Effective Computational Strategies for Determining Structures of Carcinogen-Damaged DNA. / Broyde, S.; Hingerty, B. E.

In: Journal of Computational Physics, Vol. 151, No. 1, 01.05.1999, p. 313-332.

Research output: Contribution to journalArticle

@article{2ddfdf66bdf34f87afe55974b8aa3ba1,
title = "Effective Computational Strategies for Determining Structures of Carcinogen-Damaged DNA",
abstract = "To determine three-dimensional conformations of DNA damaged by environmental chemical carcinogens, effective molecular mechanics search techniques have been developed to deal with the large system sizes and computational demands. First, extensive surveys of the potential energy surface are carried out by energy minimization. These search strategies rely on (1) using the reduced variable domain of torsion-angle (rather than Cartesian) space, (2) building larger units (about 12 base pairs) on the basis of structures of small modified subunits, and (3) employing penalty functions to search for selected hydrogen bonding patterns and to incorporate interproton distance bounds when available from experimental high-resolution nuclear magnetic resonance (NMR) studies. Second, molecular dynamics simulations with solvent can subsequently be employed to probe conformational features in the presence of polymerase enzyme responsible for DNA replication, using structures computed in the energy minimization searches as initial coordinates. A key structure-function relationship involving mirror-image molecules with very differing experimentally determined tumorigenic potencies has been deduced: the members of the pairs align oppositely when bound to DNA, making it likely that their treatment by replication and repair enzymes differ. This opposite orientation phenomenon, first predicted computationally (Singhet al., 1991), has been observed in experimental high-resolution NMR studies combined with our molecular mechanics computations in a number of different examples and has recently been confirmed experimentally in other laboratories as well (reviewed in Geacintovet al., 1997). Elucidation of this conformational feature has paved the way to uncovering the structural origin underlying very different biological outcomes stemming from chemically identical but mirror-image molecules.",
keywords = "Carcinogen-DNA structures, Molecular dynamics, Molecular mechanics",
author = "S. Broyde and Hingerty, {B. E.}",
year = "1999",
month = "5",
day = "1",
doi = "10.1006/jcph.1998.6172",
language = "English (US)",
volume = "151",
pages = "313--332",
journal = "Journal of Computational Physics",
issn = "0021-9991",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Effective Computational Strategies for Determining Structures of Carcinogen-Damaged DNA

AU - Broyde, S.

AU - Hingerty, B. E.

PY - 1999/5/1

Y1 - 1999/5/1

N2 - To determine three-dimensional conformations of DNA damaged by environmental chemical carcinogens, effective molecular mechanics search techniques have been developed to deal with the large system sizes and computational demands. First, extensive surveys of the potential energy surface are carried out by energy minimization. These search strategies rely on (1) using the reduced variable domain of torsion-angle (rather than Cartesian) space, (2) building larger units (about 12 base pairs) on the basis of structures of small modified subunits, and (3) employing penalty functions to search for selected hydrogen bonding patterns and to incorporate interproton distance bounds when available from experimental high-resolution nuclear magnetic resonance (NMR) studies. Second, molecular dynamics simulations with solvent can subsequently be employed to probe conformational features in the presence of polymerase enzyme responsible for DNA replication, using structures computed in the energy minimization searches as initial coordinates. A key structure-function relationship involving mirror-image molecules with very differing experimentally determined tumorigenic potencies has been deduced: the members of the pairs align oppositely when bound to DNA, making it likely that their treatment by replication and repair enzymes differ. This opposite orientation phenomenon, first predicted computationally (Singhet al., 1991), has been observed in experimental high-resolution NMR studies combined with our molecular mechanics computations in a number of different examples and has recently been confirmed experimentally in other laboratories as well (reviewed in Geacintovet al., 1997). Elucidation of this conformational feature has paved the way to uncovering the structural origin underlying very different biological outcomes stemming from chemically identical but mirror-image molecules.

AB - To determine three-dimensional conformations of DNA damaged by environmental chemical carcinogens, effective molecular mechanics search techniques have been developed to deal with the large system sizes and computational demands. First, extensive surveys of the potential energy surface are carried out by energy minimization. These search strategies rely on (1) using the reduced variable domain of torsion-angle (rather than Cartesian) space, (2) building larger units (about 12 base pairs) on the basis of structures of small modified subunits, and (3) employing penalty functions to search for selected hydrogen bonding patterns and to incorporate interproton distance bounds when available from experimental high-resolution nuclear magnetic resonance (NMR) studies. Second, molecular dynamics simulations with solvent can subsequently be employed to probe conformational features in the presence of polymerase enzyme responsible for DNA replication, using structures computed in the energy minimization searches as initial coordinates. A key structure-function relationship involving mirror-image molecules with very differing experimentally determined tumorigenic potencies has been deduced: the members of the pairs align oppositely when bound to DNA, making it likely that their treatment by replication and repair enzymes differ. This opposite orientation phenomenon, first predicted computationally (Singhet al., 1991), has been observed in experimental high-resolution NMR studies combined with our molecular mechanics computations in a number of different examples and has recently been confirmed experimentally in other laboratories as well (reviewed in Geacintovet al., 1997). Elucidation of this conformational feature has paved the way to uncovering the structural origin underlying very different biological outcomes stemming from chemically identical but mirror-image molecules.

KW - Carcinogen-DNA structures

KW - Molecular dynamics

KW - Molecular mechanics

UR - http://www.scopus.com/inward/record.url?scp=0009523933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0009523933&partnerID=8YFLogxK

U2 - 10.1006/jcph.1998.6172

DO - 10.1006/jcph.1998.6172

M3 - Article

VL - 151

SP - 313

EP - 332

JO - Journal of Computational Physics

JF - Journal of Computational Physics

SN - 0021-9991

IS - 1

ER -