Biomedical subjects
N Pattabiraman
Publications and source records attributed to N Pattabiraman.
Spermine-DNA interactions: a theoretical study.
Models for the interaction of spermine and DNA were studied by performing conformational energy calculations on spermine and molecular mechanics calculations on major and minor groove complexes of spermine and oligomers of DNA. Docked into the major groove of B-DNA, spermine stabilizes the complex by maximizing interactions between proton acceptors on the oligomer and proton donors on spermine. This is achieved by bending the major groove of DNA over spermine and altering oligomer sugar puckering and interstrand phosphate distances. By comparison, Liquori's minor groove model appears to be less stable than the major groove model. This evidence favors a preferential binding of spermine to certain sites in DNA, which provides a powerful force for the modification of DNA conformation.
Molecular mechanical studies of d(CGTACG)2: complex of triostin A with the middle A - T base pairs in either Hoogsteen or Watson-Crick pairing.
Computer graphics model building and molecular mechanical calculations have been carried out on d(CGTACG)2 and its bis-intercalation complexes with triostin A and an N-Me-Ala analogue of triostin A. Two conformations of the DNA have been considered both for the uncomplexed and for complexed nucleic acid: in one the central A - T base pairs are Watson-Crick base paired; in the other they are Hoogsteen base paired. The calculations offer a clear explanation why Hoogsteen base pairing is not favorable in isolated A + T-rich DNA and also suggest reasons why the bis-intercalation of triostin A might help stabilize the neighboring A - T base pairs into a Hoogsteen form. To our knowledge, this is the first study to use molecular mechanical and dynamical methods to investigate the bis-intercalator-DNA complex.
On loop folding in nucleic acid hairpin-type structures.
In a series of studies, combining NMR, optical melting and T-jump experiments, it was found that DNA hairpins display a maximum stability when the loop part of the molecule comprises four or five nucleotide residues. This is in contrast with the current notion based on RNA hairpin studies, from which it had been established that a maximum hairpin stability is obtained for six or seven residues in the loop. Here we present a structural model to rationalize these observations. This model is based on the notion that to a major extent base stacking interactions determine the stability of nucleic acid conformations. The model predicts that loop folding in RNA is characterized by an extension of the base stacking at the 5'-side of the double helix by five or six bases; the remaining gap can then easily be closed by two nucleotides. Conversely, loop folding in DNA is characterized by extending base stacking at the 3'-side of the double helical stem by two or three residues; again bridging of the remaining gap can then be achieved by one or two nucleotides. As an example of loop folding in RNA the anticodon loop of yeast tRNAPhe is discussed. For the DNA hairpin formed by d(ATCCTAT4TAGGAT) it is shown that the loop structure obtained from molecular mechanics calculations obeys the above worded loop folding principles.
Theoretical models of spermine/DNA interactions.
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Flexibility of 3',5' deoxyribonucleoside diphosphates.
In 3',5' deoxyribonucleoside diphosphates, in addition to the nature of the base and the sugar puckering, there are six single bond rotations. However, from the analysis of crystal structure data on the constituents of nucleic acids, only three rotational angles, that are about glycosyl bond, about C4'-C5' and about C3'-O3' bonds, are flexible. For a given sugar puckering and a base, potential energy calculations using non-bonded, electrostatic and torsional functions were carried out by varying the three torsion angles. The energies are represented as isopotential energy surfaces. Since the availability of the real-time color graphics, it is possible to analyse these isopotential energy surfaces. The calculations were carried out for C3' exo and C3' endo puckerings for deoxyribose and also for four bases. These calculations throw more light not only on the allowed regions for the three rotational angles but also on the relationships among them. The dependence of base and the puckering of the sugar on these rotational angles and thereby the flexibility of the 3',5' deoxyribonucleoside diphosphates is discussed. From our calculations, it is now possible to follow minimum energy path for interconversion among various conformers.
Proline-containing beta-turns in peptides and proteins: analysis of structural data on globular proteins.
Tetrapeptide sequences of the type Z-Pro-Y-X were obtained from the crystal structure data on 34 globular proteins, and used in an analysis of the positional preferences of the individual amino acid residues in the beta-turn conformation. The effect of fixing proline as the second position residue in the tetrapeptide sequence was studied by comparing the data obtained on the positional preferences with the corresponding data obtained by Chou and Fasman using the Z-R-Y-X sequence, where no particular residue was fixed in any of the four positions. While, in general, several amino acid residues having relatively very high or very low preferences for specific positions were found to be common to both the Z-Pro-Y-X and Z-R-Y-X sequences, many significant differences were found between the two sets of data, which are to be attributed to specific interactions arising from the presence of the proline residue.
An iterative approach to placing counterions around DNA.
An iterative approach, in which the effect of placing counter ions around DNA influences the electrostatic potential that the other subsequently approaching ions feel, has been used to place sodium ions around polynucleotides. The main focus of this report is to study the sequence and structure dependence on the distribution of ions around DNA, particularly that of tightly bound ions. The interesting results of the calculations are that there is significant sequence dependence on the electrostatic potentials in the B form of DNA, whereas relatively less difference in A form. In the case of Z form, the cations bridge the inter-stand phosphates along the minor groove.
Biochemical basis of the regulatory role of polyadenosine diphosphoribose.
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Steric inhibition of phenylboronate complex formation of 2'-(5"-phosphoribosyl)-5'-AMP.
Unlike all other adenine nucleotides which contain cis-diols in their ribose groups, the degradation product of polyadenosine diphosphoribose, 2'-(5"-phosphoribosyl)-5'-AMP, does not bind to boronate affinity columns. This anomalous behavior occurs even under conditions of high ionic strength (1 M salt), indicating that the absence of binding is not due to generalized repulsion between the negatively charged phosphate groups of 2'-(5"-phosphoribosyl)-5'-AMP and the negatively charged boronate sites of the resin. Despite the lack of boronate binding the presence of a chemically functional cis-diol group in 2'-(5"-phosphoribosyl)-5'-AMP was verified by quantitative periodate oxidation. Subsequent dephosphorylation rendered the cis-diol in ribosyladenosine accessible to binding to the boronate sites; therefore, one or both of the phosphate groups sterically interfere with complexation of the cis-diol with boronate. Computer model-building studies based on NMR data implicate the 5'-phosphate group of the molecule, is located sterically near the cis-diol group, inhibiting the complex formation with boronate.
Structure of DNA predicted from stereochemistry of nucleoside derivatives.
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Some implications of an alternative structure for DNA.
We have constructed a space-filling (Corey-Pauling-Koltun) model of an alternative structure for DNA. This structure is not a double helix, but consists of a pair of polynucleotide strands lying side by side and held together by Watson-Crick base pairing. Each of the two strands has alternating right- and left-handed helical segments approximately five base pairs in length. Sugar residues in alternating segments along a strand point in opposite directions. A structure slightly different from the present one proposed earlier by ourselves and another group and in which sugars in a strand all point in the same direction is ruled out. The present structure yields natural solutions to the problems of supercoiling of DNA and of strand separation during DNA replication. This model is energetically more favorable than the double helix.
Occluded molecular surface: analysis of protein packing.
We describe a novel method to calculate the packing interactions in protein structural models. The method calculates the interatomic occluded surface areas for each atom in the protein model. The identification of, and degree of interaction with, neighboring atoms is accomplished by extending surface normals from a dot surface of each atom to the point of intersection with neighboring atoms. The combined occluded and non-occluded surface areas may be normalized for the amino acid composition of the protein providing a single parameter, the normalized protein surface ratio, which is diagnostic for native-like structures. Individual residues in the model which are in infrequent occluded surface environments may be identified. The method provides a means to explicitly describe packing densities and packing environments of individual atoms in a protein model. Finally, the method allows estimation of the complementarity between any interacting molecules, for example a ligand binding to a receptor.