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Biomedical subjects

M Sundaralingam

Publications and source records attributed to M Sundaralingam.

18 recordsLinked to original sources
PubMed1992

Crystal and molecular structure of d(GTGCGCAC): investigation of the effects of base sequence on the conformation of octamer duplexes.

The structure of the self-complementary deoxyoctanucleotide d(GTGCGCAC), which crystallized as an A-type helix in the space group P4(3)2(1)2, with one strand in the crystallographic asymmetric unit has been determined and refined to a final R-value of 0.154 using 1.64-A diffraction data collected on an area detector. In contrast to the closely related sequence d(GTGTACAC)tet, there was no evidence for an ordered spermine molecule in the major groove of this octamer. Ordered water is found associated with almost all the exposed hydrogen bonding groups of the octamer. A pentagonal ring of water molecules is hydrogen bonded to O6 and N7 of G3 and the N4 and O6 of the C4.G13 base pair. A detailed comparison of the local helical parameters of d(GTGCGCAC) and d(GTGTACAC)tet is presented. The base sequence change at the center of the octamers affects several of the local helical parameters, via both intra- and interduplex interactions within the crystal.

Base Composition↗
PubMed1992

Crystal and molecular structure of the alternating dodecamer d(GCGTACGTACGC) in the A-DNA form: comparison with the isomorphous non-alternating dodecamer d(CCGTACGTACGG).

The crystal structure of the alternating dodecamer d(GCGTACGTACGC) (5'-GC) has been determined to a resolution of 2.55A using oscillation film data. The crystals belong to space group P6(1) 22, a = b = 46.2A, c = 71.5A with one strand in the asymmetric unit, and are isomorphous with a previously described non-alternating dodecamer, d(CCGTACGTACGG) (5'-CC). Refinement by X-PLOR/NUCLSQ gave a final R factor of 14.2% for 1089 observations. The molecule adopts the A-DNA form. The interchange of the terminal base pairs in the two dodecamers results in differences in the intermolecular contacts and may account for the differences in the bending. This dodecamer shows an axial deflection of 30 degrees, in the direction of the major groove compared to 20 degrees in 5'-CC and may be a consequence of additional contacts generated in 5'-GC by the interchange of end base pairs. The high helical axis deflection appreciably influences the local helical parameters. The molecule exhibits relatively high inclination angles, and has a narrow major groove. The helical parameters when described relative to the dyad-related hexamer halves of the molecule give more reasonable values. The crystal packing, local helical parameters, torsion angles, and hydration are described and also compared with the non-alternating 5'-CC dodecamer.

Amides↗
PubMed1992

Crystal and molecular structure of the A-DNA dodecamer d(CCGTACGTACGG). Choice of fragment helical axis.

The crystal structure of the dodecamer d(CCGTACGTACGG) has been determined at 2.5 A resolution. The crystals grow in the hexagonal space group P6(1)22, a = b = 46.2 A, c = 71.5 A with one strand as the asymmetric unit. Diffraction data were collected by the oscillation film method yielding 1664 unique reflections with an Rmerge of 0.04. The structure was solved by real-space rotational translational searches with idealized helical models of A, B and Z-DNA. The best agreement was given by an A-DNA model with its dyad axis along the diagonal crystallographic dyad axis, with an R-factor 0.43 and correlation coefficient of 0.59 for data between 10 and 5 A. Iterative map fitting and restrained least-squares refinement and addition of 40 solvent molecules brought the R-factor to 0.15 and the correlation coefficient to 0.97 for all data between 8.0 and 2.5 A. The stereochemistry of the atomic model is good, with a root-mean-square deviation in bond distances of 0.006 A. This is the first example of an A-DNA containing a full helical turn. The dodecamer displays a novel packing motif. In addition to the characteristic contacts between the terminal base-pairs and the minor grooves of symmetry-related molecules, there are also minor groove to minor groove interactions not previously observed. The packing leaves an approximately 25 A diameter solvent channel around the origin, along the c-axis. The presence of a prominent 3.4 A meridional reflection and other diffuse features in the diffraction pattern provided evidence for the presence of disordered B-DNA along the c-axis, which can be accommodated in these solvent channels. The molecular conformation of the dodecamer also displays novel features. The dyad-related halves of the molecule are bent at an angle of 20 degrees, and the helical parameters are affected by this bend. Unlike the shorter A-DNA octamers, the dimensions of the major groove can be directly measured. Novel correlations between local helical parameters and global conformational features are presented. Most of the solvent molecules are associated with the major groove and the sugar-phosphate backbone.

Base Sequence↗
PubMed1992

Structure of the anti-malarial drug primaquine diphosphate.

8-(4-Amino-1-methylbutylamino)-6-methoxyquinoline bis(dihydrogenphosphate), C15H23N3O2+.2(H2PO4)-, Mr = 455.35, triclinic, P1, Z = 2, a = 7.389 (6), b = 8.862 (4), c = 16.055 (10) A, alpha = 97.57 (2), beta = 100.21 (3), gamma = 77.01 (2) degrees, V = 1003.6 (5) A3, Dm = 1.495 (by flotation), Dx = 1.507 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu(Cu K alpha) = 24.48 cm-1, F(000) = 480, room temperature, R = 0.068 for 3448 observed reflections. The above working cell is related to the reduced cell with angles alpha = 82.43, beta = 79.79 and gamma = 77.01 degrees by the transformation (-100/0 -10/001). Primaquine diphosphate was crystallized in the dicationic form with protonation on the quinoline ring nitrogen atom and on the terminal amino group. One dihydrogenphosphate anion is chelated by the quinoline ring and the butylamino side chain. The other dihydrogenphosphate anion is hydrogen bonded to the terminal amino group. The C(14) atom is nearly in the plane of the quinoline ring with a C(9)-C(8)-N(13)-C(14) torsion angle of 169 degrees. The butyl-diamino side chain is kinked by rotation about the C(14)-C(16) bond with a N(13)-C(14)-C(16)-C(17) torsion angle of -59 degrees. The C(15) methyl substituent is in line with the rest of the butyl chain. The terminal amino group N(19) is hydrogen bonded to three symmetry-related phosphate groups while N(1) and N(13) are 'chelated' to a fourth phosphate group.

Antimalarials↗
PubMed1992

Crystal structure of the Y52F/Y73F double mutant of phospholipase A2: increased hydrophobic interactions of the phenyl groups compensate for the disrupted hydrogen bonds of the tyrosines.

The enzyme phospholipase A2 (PLA2) catalyzes the hydrolysis of the sn-2 ester bond of membrane phospholipids. The highly conserved Tyr residues 52 and 73 in the enzyme form hydrogen bonds to the carboxylate group of the catalytic Asp-99. These hydrogen bonds were initially regarded as essential for the interfacial recognition and the stability of the overall catalytic network. The elimination of the hydrogen bonds involving the phenolic hydroxyl groups of the Tyr-52 and -73 by changing them to Phe lowered the stability but did not significantly affect the catalytic activity of the enzyme. The X-ray crystal structure of the double mutant Y52F/Y73F has been determined at 1.93 A resolution to study the effect of the mutation on the structure. The crystals are trigonal, space group P3(1)21, with cell parameters a = b = 46.3 A and c = 102.95 A. Intensity data were collected on a Siemens area detector, 8,024 reflections were unique with an R(sym) of 4.5% out of a total of 27,203. The structure was refined using all the unique reflections by XPLOR to a final R-factor of 18.6% for 955 protein atoms, 91 water molecules, and 1 calcium ion. The root mean square deviation for the alpha-carbon atoms between the double mutant and wild type was 0.56 A. The crystal structure revealed that four hydrogen bonds were lost in the catalytic network; three involving the tyrosines and one involving Pro-68. However, the hydrogen bonds of the catalytic triad, His-48, Asp-99, and the catalytic water, are retained. There is no additional solvent molecule at the active site to replace the missing hydroxyl groups; instead, the replacement of the phenolic OH groups by H atoms draws the Phe residues closer to the neighboring residues compared to wild type; Phe-52 moves toward His-48 and Asp-99 of the catalytic diad, and Phe-73 moves toward Met-8, both by about 0.5 A. The closing of the voids left by the OH groups increases the hydrophobic interactions compensating for the lost hydrogen bonds. The conservation of the triad hydrogen bonds and the stabilization of the active site by the increased hydrophobic interactions could explain why the double mutant has activity similar to wild type. The results indicate that the aspartyl carboxylate group of the catalytic triad can function alone without additional support from the hydrogen bonds of the two Tyr residues.

Amino Acid Sequence↗
PubMed1979

Conformational analysis of arabinonucleosides and nucleotides. A comparison with the ribonucleosides and nucleotides.

Conformations of arabino nucleosides and nucleotides have been analyzed by semiempirical energy calculations. It is found that the change in the configuration of the O(2')-hydroxyl group in arabinoses compared to riboses exerts significant influence on the conformational priorities of the glycosyl and the exocyclic C(4')-C(5') bond torsions. While the anti conformations for the bases are preferred, the anti in equilibrium or formed from syn interconversion is considerably hampered compared to ribosides due to large energy barrier. Further the preferred anti glycosyl torsions are shifted to higher values for C(3')-endo puckers and in ribosides. While the gauche+ conformation around the C(4')-C(5') bond is favored for C(3')-endo arabinosides, it is strongly stabilized for C(2')-endo arabinosides only in the presence of the intrasugar hydrogen bond O(2')-H ... O(5'). The net attractive electrostatic interactions between the phosphate and the base stabilizes the preferred conformations of 5'-arabinonucleotides also.

Arabinonucleosides↗
PubMed1978

Zwitterionic character of nucleotides: possible significance in the evolution of nucleic acids.

X-ray crystallography has shown that the free acids of adenosine 5'- and 3'-monophosphates and of cytidine 5'- and 3'-monophosphates exist as zwiterions in the solid state with protonation of the adenine base at the N(1) site and of the cytosine base at the corresponding site N(3) and the phosphate group negatively charged. In this paper, evidence is presented for the zwitterionic character of the free acids of the monomeric nucleotides guanosine 5'-monophosphate and inosine 5'-monophosphate with protonation of the base at the N(7) site of the imidazole moiety.

Adenosine Monophosphate↗
PubMed1978

Stacking of Crick Wobble pair and Watson-Crick pair: stability rules of G-U pairs at ends of helical stems in tRNAs and the relation to codon-anticodon Wobble interaction.

The occurrence of the noncomplementary G-U base pair at the end of a helix is found to be governed by stacking interactions. As a rule, a G-U pair with G on the 5'-side of a Watson-Crick base pair exhibits strikingly greater stacking overlap with the Watson-Crick base pair than a G-U pair on the 3'-side of a Watson-Crick base pair. The former arrangement is expected to be more stable and indeed is observed 29 times out of 32 in the known transfer RNA molecules. In accordance with this rule, the major wobble base pairs G-U or I-U in codon-anticodon interactions have G or I on the 5'-side of the anticodon. Similarly, in initiator tRNAs, this rule is obeyed where now the G is the first letter of the codon (5'-side). In the situation where U is in the wobble position of the anticodon, it is usually substituted at C(5) andmay also have a 2-thio group and it can read one to four codons depending on its modifications. A G at the wobble position of the anticodon can recognize the two codons ending with U or C and modification of G (unless it is I) does not change its reading properties.

Anticodon↗
PubMed1976

Mechanisms of chain folding in nucleic acids. The (omega, omega) plot and its correlation to the nucleotide geometry in yeast tRNAPhe1.

The (omega', omega) polot depicting the internucleotide P-O bond rotation angles in yeast phenylalanyl transfer RNA has established the interdependence of the phosphodiesters and the nucleotide geometries in the folding of the polynucleotide backbone. The plot distinguishes the regions characteristic of secondary helical structures and tertiary structural loops and bends. The folding of the polynucleotide chain is accomplished either solely by rotations around the P-O bonds or in concert with rotations around the nucleotide C4'-C5' bond with or without changes in the sugar ring pucker. In spite of differences in nucleotide sequence and intraloop tertiary interactions in the anticodon and pseudouridine loops, a characteristic repeating structural unit is found for the sugar-phosphate backbone of the tetranucleotide segment around the sharp turns.

Anticodon↗
PubMed1976

Structlre of transfer RNA molecules containing the long variable loop.

A structure is proposed for the type II tRNA molecules containing the long variable loop and the tertiary base interactions here are compared with type I tRNAs having the short variable loop. The type II tRNAs are similar to the type I tRNAs in their tertiary base pairing interactions but differ from them generally by not having the tertiary base triples. The long variable loop, which is comprised of a helical stem and a loop at the end of it, emerges from the deep groove side of the dihydrouridine helix, and is tilted roughly 30 degrees to the plane formed by the amino acid-pseudo-uridine and anticodon-dihydrouridine helices found in yeast tRNAPhe. The fact that many of the type I tRNAs also lack the full compliment of base triples suggests that the tertiary base pairs may alone suffice to sustain the tRNA fold required for its biological function. The base triples and the variable loop appear to have little functional significance. The base type at position 9 is correlated with the number of base triples and G-C base pairs in the dihydrouridine stem.

Base Sequence↗
PubMed1976

Analysis of the possible helical structures of nucleic acids and polynucleotides. Application of (n-h) plots.

The two helical parameters n and h where n is the number of nucleotide residues per turn and h is the height per nucleotide residue have been evaluated for single stranded helical polynucleotide chains comprising C(3') -endo and C(2') endo class of nucleotides. The helical parameters are found to be especially sensitive to the C(4')-C(3') (sugar pucker) and the C(4')-C(5') torsions. The (n-h) plots display only one important helix forming domain for each class of nucleotides characterized by the sugar pucker and the C(4')-C(5') torsion. A correlation between the (n-h) plots and the known RNA (A,A') and DNA (A,B,C) helical forms has been established. It is found that all forms of helices except the C-DNA possess a favorable combination of P-O torsions. The analysis of the (n-h) plots suggests that C-DNA can have a conformation very similar to B-DNA. Although the (n-h) plots predict the stereochemical possibility of both right-handed and left-handed helices, nucleic acids apparently prefer right-handed conformation because of the energetics associated with the sugar-phosphate backbone and the base.

Binding Sites↗
PubMed1976

Atomic coordinates and molecular conformation of yeast phenylalanyl tRNA. An independent investigation.

The atomic coordinates of yeast tRNA(Phe) in the monoclinic crystal form have been determined by an independent analysis from a model built into a 3 A MIR map. The overall molecular structure is found to be in agreement with those reported for the same crystal form by Ladner et al. (1975) and for the orthorhombic form by Quigley et al. (1975) and Kim et al. (1975). However, significant differences between any two of the four models are found in certain local regions of the molecule. The structure is analyzed in terms of the nucleotide stereochemistry and internucleotide phosphodiesters. A striking observation is that the majority of the nucleotide moieties occur in the conformation preferred by the constituent mononucleotides themselves. The internucleotide P-O bonds afford the primary source of flexibility for the folding of the polynucleotide backbone while the sugar pucker and C(4')-C(5') torsions provide the secondary source of flexibility.

Binding Sites↗