An ab initio quantum mechanics calculation that correlates with ligand orientation and DNA cleavage site selectivity in camptothecin-DNA-topoisomerase I ternary cleavage complexes

Xiangshu Xiao, Mark Cushman

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53 Citations (Scopus)

Abstract

Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only π-π stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experimental binding orientation of CPT at the cleavage site but also shows very good correlation between the binding energy for different sequences and the observed frequency of CPT-stabilized sites in the SV40 viral genome. Therefore, it can be concluded that hydrogen bonding of the ligand to the surrounding amino acid residues of the protein is of minor significance. The present method should be applicable to other polycyclic top1 inhibitors.

Original languageEnglish (US)
Pages (from-to)9960-9961
Number of pages2
JournalJournal of the American Chemical Society
Volume127
Issue number28
DOIs
StatePublished - Jul 20 2005
Externally publishedYes

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Camptothecin
Type I DNA Topoisomerase
DNA Cleavage
Quantum theory
DNA sequences
Mechanics
DNA
Ligands
Alkaloids
X ray crystallography
Binding energy
Amino acids
Hydrogen bonds
Genes
Derivatives
Proteins
Camptotheca
Viral Genome
X Ray Crystallography
Hydrogen Bonding

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

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title = "An ab initio quantum mechanics calculation that correlates with ligand orientation and DNA cleavage site selectivity in camptothecin-DNA-topoisomerase I ternary cleavage complexes",
abstract = "Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only π-π stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experimental binding orientation of CPT at the cleavage site but also shows very good correlation between the binding energy for different sequences and the observed frequency of CPT-stabilized sites in the SV40 viral genome. Therefore, it can be concluded that hydrogen bonding of the ligand to the surrounding amino acid residues of the protein is of minor significance. The present method should be applicable to other polycyclic top1 inhibitors.",
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AU - Xiao, Xiangshu

AU - Cushman, Mark

PY - 2005/7/20

Y1 - 2005/7/20

N2 - Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only π-π stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experimental binding orientation of CPT at the cleavage site but also shows very good correlation between the binding energy for different sequences and the observed frequency of CPT-stabilized sites in the SV40 viral genome. Therefore, it can be concluded that hydrogen bonding of the ligand to the surrounding amino acid residues of the protein is of minor significance. The present method should be applicable to other polycyclic top1 inhibitors.

AB - Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only π-π stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experimental binding orientation of CPT at the cleavage site but also shows very good correlation between the binding energy for different sequences and the observed frequency of CPT-stabilized sites in the SV40 viral genome. Therefore, it can be concluded that hydrogen bonding of the ligand to the surrounding amino acid residues of the protein is of minor significance. The present method should be applicable to other polycyclic top1 inhibitors.

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