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Biomedical subjects

A Dearing

Publications and source records attributed to A Dearing.

6 recordsLinked to original sources
PubMed1988

Computer-aided molecular modelling: research study or research tool?

Developments in computational methods and equipment have produced a new type of research chemist, who prefers to calculate properties as well as measure them, either to gain a better understanding of microscopic molecular behaviour per se, or to guide a broader scientific study using a so-called 'rational' approach. While there is good reason to believe that significant results can be obtained this way, it is clear that only some of the 'tools of the trade' are sufficiently robust to present to those who are not experts in the field. This paper discusses the underlying basis for molecular modelling techniques, describing their history, state of maturity and prospects for future development. The intention is to outline the scope that these play in an industrial research environment, and to examine how they can successfully be incorporated as routine research tools. Computer-based molecular modelling is not a unique discipline. Some comparisons are drawn between it and other computer-based techniques that have reached a greater degree of maturity, in order to highlight the points made.

Computer Simulation↗
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↗
PubMed1981

Molecular mechanical studies of proflavine and acridine orange intercalation.

Previous workers have reported that proflavine and acridine orange form various structurally different complexes with the dinucleoside phosphates rCpG and dCpG, with uniform C3'-endo and mixed C3'-endo (3'-5') C2'-endo sugar puckers being observed. We present theoretical calculations, based on the method of molecular mechanics, which support the experimental observations. The results suggest that the mixed C3'-edo (3'-5') C2'-endo pucker conformation isi intrinsically more stable than the uniform C3'-endo conformation, but that the additional stabilisation gained from specific, hydrogen bonding, interactions between nucleic acid and solvent, or intramolecularly within the nucleic acid, can lead to the adoption of the latter conformation, or of variants between the two. The role played by hydrogen bonding between amino-groups and nucleic acid phosphate appears more subtle than previously supposed.

Acridine Orange↗
PubMed1981

Theoretical studies of the structure and energies of base-paired nucleotides and the dissociation kinetics of a proflavine-dinucleotide complex.

We presented calculations of base-paired dinucleoside phosphates and hexanucleoside pentaphosphates of varying compositions. Complete energy minimizations were performed for (a) the ten base-pair combinations of dinucleoside phosphates, starting from a B-DNA conformation, (b) six hexanucleoside pentaphosphates--base-paired CGCGCG, GCGCGC, G6-C6, TATATA, ATATAT, and A6-T6--starting with a B-DNA geometry, and (c) the four hexanucleoside pentaphosphates that have alternating pyrimidine-purine sequences, starting with a Z-DNA geometry. In addition, we studied the proflavine-base-paired CpG complex, using both complete energy minimization and energetic constraints to force the drug to dissociate from the dinucleoside phosphate. In many of these calculations, we examined the dependence of the calculated energies and structures on the potential function, focusing mainly on the effect of nonbonded potentials, the effective dielectric constant, and the role of counterions. These calculations allow us to explain why pur-(3',5')-pyr sequence isomers are more stable than pyr-(3'-5')-pur isomers. Both base-base and base-backbone energies are important in this differentiation, with the former being mainly van der Waals attraction and the latter mainly electrostatic energies. The calculations also allow us to understand the differences in double helical stabilities found by Wells et al. These differences, caused by electrostatic interactions between those bases not Watson-Crick hydrogen bonded, allow us to explain the following experimental data: poly(dG-dC) melts 12 degrees C higher than poly dG-poly dC, poly(dA-dT) melts 6 degrees C lower than poly dA-poly dT, and poly(dA-dG)-poly(dC-dT) melts 6 degrees C lower than poly(dA-dC)-poly(dT-dG). These results have interesting implications for drug binding: they imply that simple intercalators, such as ethidium, will exhibit a greater affinity for hetero- than for homopolymers and that this preference will be greater in the AT polymers than it is in the GC polymers. Our calculations allow us to explain the fact that Z-DNA is more stable than B-DNA under high salt conditions and to suggest some sequence dependence for the Z to B transition. We found that the activation energy for proflavine dissociating from dCpG is almost equal to the dissociation energy.

Acridines↗