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T Lybrand

Publications and source records attributed to T Lybrand.

6 recordsLinked to original sources
PubMed1989

A combined 2D-NMR and molecular dynamics analysis of the structure of the actinomycin D: d(ATGCAT)2 complex.

We present a comparative analysis of an NMR experiment and molecular and harmonic dynamics simulations of an actinomycin D: d(ATGCAT)2 complex. A comparison of NOE measurements and 1/R6 weighted proton-proton distances confirm the general correctness of the Actinomycin D-DNA model proposed by Sobell. There are, however, some substantial differences between the proton-proton distances inferred from the NOE results and the molecular and harmonic dynamics simulations. The remaining discrepancies could either come from contributions of other conformations to the average properties of the complex or from uncertainties in the NMR distance analysis. An analysis of the molecular dynamics helix properties, sugar puckers, hydrogen bonding, rms fluctuations and torsional properties are qualitatively consistent with those from previous simulations, but the presence of an intercalated drug leads to some new structural and dynamical features.

Chemical Phenomena↗
PubMed1989

Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA.

We present molecular mechanics simulations on models of covalent complexes between the diol-epoxides of the carcinogens benzo[a]pyrene, benzo[e]pyrene and benzo[c]phenanthrene and a DNA pentamer d(GCGCG).d(CGCGC). In all the models, the carcinogen diol-epoxides lie in the minor groove with alkylation to the exocyclic amino group of the guanine. The theoretical calculations on the benzo[a]pyrene adducts to the pentamer are qualitatively consistent with the experimentally observed relative reactivities between various isomers. The adduct with the (+)trans isomer, which is the most carcinogenic of the benzo[a]pyrene stereoisomers, is calculated to be the energetically most favored. The relative energetic preferences in the adducts of benzo[e]pyrene diol-epoxides to the pentanucleotide parallel those of benzo[a]pyrene. However, there is no obvious explanation for the lack of biological activity in the diol-epoxides of the former carcinogen from the theoretical calculations. In the case of adducts with the diol-epoxides of benzo[c]phenanthrene, the energetically most favored structures are isomers with significant biological activity. The distortions in the double helix are more significant in the complexes with the diol-epoxides of this carcinogen compared to those in the complexes with the diol-epoxides of the other two carcinogens.

Benzo(a)pyrene↗
PubMed1986

Modeling complex molecular interactions involving proteins and DNA.

We have presented a perspective of progress in three areas of simulations of complex molecules: the development of force fields for molecular simulation; the application of computer graphics, molecular mechanics and molecular dynamics in simulations of DNA and DNA-drug complexes and the application of computer graphics, molecular mechanics and quantum mechanics in studies of enzyme substrate interactions. It is our perspective that improvements are being made in force fields, and these will allow a more accurate simulation of structures and energies of complex molecules. In the area of DNA molecular mechanics and dynamics, it is clear that the use of computer graphics model building combined with NMR NOE data is a potentially very powerful tool in accurately determining structures of drug-DNA complexes using molecular mechanics and dynamics. Finally, we are in a position to reasonably simulate structures and (qualitatively) energies for complete reaction pathways of enzymes using a combination of computer graphics, molecular mechanics and quantum mechanics. More accurate energies and pathways are sure to follow, using the combined molecular mechanics/quantum mechanics optimization developed by Singh and the free energy perturbation methods pioneered in Groningen and Houston.

Base Sequence↗
PubMed1981

A molecular mechanical study of complexes formed between 4-nitroquinoline-N-oxide and dinucleoside phosphates.

Molecular mechanical calculations were done on complexes of 4-nitroquinoline-N-oxide (NQO) with various dinucleoside phosphates [(ApT)2, (CpG)2, (GpC)2, and (TpA)2]. Models built using proflavine (uniform C3' endo sugar puckers) and acridine orange (mixed C3' endo (3'-5') C2' endo sugar puckers) dinucleoside phosphate X-ray structures were used in the calculations. Relative binding energies, complex geometries, and various intercalator orientations in the complexes were studied. The results suggest qualitatively different geometries for pyr-(3'-5')-pur and pur-(3'-5')-pyr sequences. Specifically, we find marked distortion in some of the complexes (i.e. there is not a parallel coplanar relationship between the base pairs and intercalator), distortion of the NQO nitro group from planarity in the complexes and mobility of NQO in the intercalation site. We suggest that experimental studies of NQO-dinucleoside phosphate complexes may reveal intercalation complexes which deviate substantially more from a nearly parallel coplanar arrangement of bases and intercalator than has been previously observed.

4-Nitroquinoline-1-oxide↗