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Query: UNIPROT:P06889 (Mol)
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A branched alpha-cyclodextrin is a derivative of an alpha-cyclodextrin with a branch consisting of an extra glucose unit. Its water solubility is considerably higher than that of the unbranched one. We have studied the high solubility of the molecule in aqueous solution by molecular dynamics simulations. Trajectories of the molecule at 293 K were calculated using GROMOS programs in three different environments, i.e., in vacuo, in the crystalline state, and in aqueous solution. A simulation in vacuo was carried out to explore stable conformations of the molecule in the isolated system. The quality of the simulations were examined by comparing the X-ray and the simulated crystal structures. The results of the simulations show three remarkable structural features of the molecule: self-inclusion with its branched portion, twist-boat conformation of a glucose ring, and wobbling of its macrocycle. Among these, the last feature is closely related to the water solubility of the molecule. The solubility of cyclodextrin appears to be mainly governed by its intramolecular interglucose hydrogen bonds, which inhibit hydration by solvent water molecules. The results of our simulations indicate that the capability to form hydrogen bonds in branched alpha-cyclodextrin decreased as the macrocycle of the molecule lost its regular circular shape. Such wobbling of the macrocycle was observed on a relatively short time scale (several picoseconds). An extra glucose unit introduced to alpha-cyclodextrin may cause the improved water solubility of the molecule through the greater wobbling motion of its macrocycle.
J Mol Graph 1994 Dec
PMID:A molecular dynamics study of branched alpha-cyclodextrin. 769 21

Mitomycin C (MC) is a potent antitumor antibiotic which alkylates DNA through covalent linkage of its C-1" position with the exocyclic N2 amino group of guanine to yield the [MC]dG adduct at the duplex level. We report on the solution structure of the monoalkylated MC-DNA 9-mer complex where the [MC]dG5 adduct is positioned opposite dC14 in the d(A3-C4-[MC]G5-T6).d(A13-C14-G15-T16) sequence context. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE intensity based refinement. The formation of the [MC]dG adduct occurs with retention of the Watson-Crick alignment at the [MC]dG5.dC14 base-pair and flanking pairs in the complex. The MC ring is positioned in the minor groove with its indoloquinone aromatic ring system at a approximately 45 degrees angle relative to the helix axis and directed towards the 3'-direction on the unmodified strand. The MC indoloquinone chromophore is asymmetrically positioned in a slightly widened minor groove so that its plane is parallel to and stacked over the d(C14-G15-T16) segment on the unmodified strand with its other face exposed to solvent. The MC five-membered ring adopts an envelope pucker with its C-2" atom displaced from the mean plane and directed away from the unmodified strand. We observe conformational perturbations in the DNA 9-mer duplex on formation of the monoalkylated MC complex. Specifically, the base-pairs are displaced by approximately -3.0 A towards the major groove on positioning the MC in the minor groove. This perturbation is accompanied by base stacking patterns similar to those observed in A-DNA while the majority of the sugars adopt puckers characteristic of B-DNA. Conformational perturbations as monitored by helix twist, sugar pucker pseudorotation and glycosidic torsion angles are also observed for the d(T6-C7-I8).d(C11-G12-A13) segment that is adjacent to but does not overlap the MC binding on the 9-mer duplex. We note that the O-10" atom on the carbamate side-chain of MC forms an intermolecular hydrogen bond with the exocyclic amino group of dG15 in two of the three refined structures of the complex. The solution structure of the complex containing this intramolecular hydrogen bond readily explains both the previously observed d(C-G).d(C-G) sequence requirement for cross-linking and the observed, somewhat less stringent, requirement of the same sequence for the initial monoalkylation step.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1995 Mar 24
PMID:Solution structure of the monoalkylated mitomycin C-DNA complex. 770 79

Four-helix bundles are identified and characterized in the subunit interfaces of protein multimers. We find that this motif occurs as often in the interfaces as in the protein monomers. Common and different characteristics demonstrated by the bundles in the two environments suggest the possible stabilization mechanisms of the bundles via cooperative helical twist, dipole alignment and interhelical connections. Nucleation of parallel helix pairs may be a favourable pathway before the pairs couple into bundles during folding. Certain properties found chaotic in the interface four-helix bundles indicate that either the subunit association is far from the global minimum conformation, or that the footprints of the folding pathway are recorded in these properties.
J Mol Biol 1995 Apr 21
PMID:A study of four-helix bundles: investigating protein folding via similar architectural motifs in protein cores and in subunit interfaces. 773 Oct 40

The use of Lennard-Jones potentials gives rise to an expected energy distribution for main-chain polypeptide conformations in the Ramachandran plot that matches well the observed distribution of phi, psi values in high-resolution proteins. The position of the energy minimum in the beta-strand conformation region is situated where there is a substantial contribution from the electrostatic attraction between the partial charge of the carbonyl carbon atom of one amino acid residue and that of the carbonyl oxygen atom of an adjacent residue. This attraction gives rise to a preference for the right-twisted beta-strand conformation compared with the left-twisted conformation. The majority of beta-sheets are twisted, almost always in one direction. Looking along a single strand, the twist is to the right. This twist also helps provide a rationale for the characteristic topology of the strand-helix-strand unit often observed in alpha/beta proteins. The electrostatic explanation for the twist we propose has not, to our knowledge, been explicitly suggested previously. The factor that has been most widely proposed to explain the twist is steric hindrance involving side-chain atoms. We provide evidence that the electrostatic effect is of comparable significance. Right-twisted beta-strands are geometrically closely related to polyproline II helices and to collagen helices, both of which are left-handed. Short regions of polyproline II type helices, which are sometimes, but not always, rich in proline residues, are common at protein surfaces. We point out that these helices are stabilised by the same carbonyl-carbonyl interactions as in right-twisted beta-strands.
J Mol Biol 1995 Apr 28
PMID:Coulombic attractions between partially charged main-chain atoms stabilise the right-handed twist found in most beta-strands. 773 47

A simple program, BEND, has been written to calculate the magnitude of local bending and macroscopic curvature at each point along an arbitrary B-DNA sequence, using any desired bending model that specifies values of twist, roll and tilt as a function of sequence. The program has been used to evaluate six different DNA bending models in three categories. Two are bent non-A-tract models: (a) A new model based on the nucleosome positioning data of Satchwell et al 1986 (J. Mol. Biol. 191, 659-675), (b) The model of Calladine et al 1988 (J. Mol. Biol. 201, 127-137). Three are bent A-tract models: (c) The wedge model of Bolshoy et al 1991 (Proc. Natl. Acad. Sci. USA 88, 2312-2316), (d) The model of Cacchione et al 1989 (Biochem. 28, 8706-8713), (e) A reversed version of model (b). The last is a junction model: (f) The model of Koo & Crothers 1988 (Proc. Natl. Acad. Sci. USA 85, 1763-1767). Although they have widely different assumptions and values for twist, roll and tilt, all six models correctly predict experimental A-tract curvature as measured by gel retardation and cyclization kinetics, but only the new nucleosome positioning model is successful in predicting curvature in regions containing phased GGGCCC sequences. This model--showing local bending at mixed sequence DNA, strong bends at the sequence GGC, and straight, rigid A-tracts--is the only model consistent with both solution data from gel retardation and cyclization kinetics and structural data from x-ray crystallography.
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PMID:Bending and curvature calculations in B-DNA. 781 43

The observed sequence dependence of the mean twist angles in 38 B-DNA crystal structures can be understood in terms of simple geometrical features of the constituent base-pairs. Structures with low twist appear to unwind in response to severe steric clashes of large exocyclic groups (such as NH2-NH2) in the major and minor grooves, while those with high twist are subjected to lesser contacts (H-O and H-H). We offer a simple clash function that depends on base-pair morphology (i.e. the chemical constitution of base-pairs) and satisfactorily accounts for the twist angles of the ten common Watson-Crick dimer steps both in the solid state and in solution. The twist-clash correlation that we find here still holds when extended to modified bases. In addition to Calladine's purine-purine clashes, we add other close contacts between bases in the grooves, and consider the conformational restrictions on the geometry of the sugar-phosphate backbone (namely, we emphasize the tendency of DNA to conserve virtual backbone length). The significance of this finding is threefold: (1) sequence-dependent DNA twisting is directly involved in protein-DNA interactions; (2) strong correlation between Twist and Roll helps to elucidate the bending of the double helix as a function of base sequence; (3) it is possible to anticipate the effects of chemical modifications on twisting and bending. The mutual correlations of other structural parameters with the twist make this angle a primary determinant of DNA conformational heterogeneity.
J Mol Biol 1995 Mar 17
PMID:B-DNA twisting correlates with base-pair morphology. 789 60

The solution structure of the d(T-C-G-A) sequence at acidic pH has been determined by a combination of NMR and molecular dynamics calculations including NOE intensity based refinements. This sequence forms a right-handed parallel-stranded duplex with C+ .C (three hydrogen bonds along Watson-Crick edge), G.G (two symmetry related N2-H.. N3 hydrogen bonds) and A.A (two symmetry related N6-H..N7 hydrogen bonds) homo base-pair formation at acidic pH. The duplex is stabilized by intra-strand base stacking at the C2-G3 step and cross-strand base stacking at the G3-A4 step. The thymine residues on partner strands are directed towards each other and are positioned over the C+ .C base-pair. All four residues adopt anti glycosidic torsion angles and C2'-endo type sugar conformations in the parallel-stranded d(T-C-G-A) duplex which exhibits large changes in twist angles between adjacent steps along the duplex. This study rules out previously proposed models for the structure of the d(T-C-G-A) duplex at acidic pH and supports earlier structural contributions, which established that d(C-G) and d(C-G-A) containing sequences at acidic pH pair through parallel-stranded alignment. We have also monitored hydration patterns in the symmetry related grooves of the parallel-stranded d(T-C-G-A) duplex.
J Mol Biol 1994 Sep 30
PMID:Solution structure of the d(T-C-G-A) duplex at acidic pH. A parallel-stranded helix containing C+ .C, G.G and A.A pairs. 793 7

An atomic model of the sickle hemoglobin (HbS) fiber was synthesized by combining the molecular coordinates of the fiber (obtained from electron microscopy) with atomic coordinates of the sickle hemoglobin double strand (obtained from X-ray crystallography). The model is stereochemically acceptable. The majority of polymerization-sensitive HbS mutants are located at fiber contact sites and the majority of the mutants that do not affect polymerization are not located at contact sites. The residues at intermolecular contacts in the fiber model are reported. We have searched the coordinate space in the vicinity of the EM reconstructions to find models with alternative sets of coordinates that satisfy the mutant data, contain 5-A contacts between double strands, and are stereochemically acceptable. This involved a systematic examination over 297 different models. The alternative fiber models were generated with a range of fiber pitch, double-strand positions, and double-strand polarity. Models which had unacceptably close contacts between atoms, failed to satisfy the mutant data, or did not have 5-A contacts between double strands were considered unacceptable. None of the acceptable alternative fiber models improved the agreement between the polymerization behavior of HbS mutants and their contact site location. However, several models could account for the polymerization data equally well. Residue locations for single-site HbS mutations that could discriminate between alternative fiber models are proposed. The twist of HbS fibers varies in an apparent random manner with an average rotation of 7.8 +/- 2.5 degrees per molecule and a maximum rotation of 16 degrees per molecule. The number of interdouble-strand contacts as a function of fiber twist shows a broad maximum around 9 degrees and may account for the observed range of fiber pitch. This study shows that the upper limit on the fiber twist could result from a loss of axial contacts and repulsive van der Waals interactions between residues involved in interstrand contacts. The loss of axial contacts limits the radial growth of the fiber. In the appendix we analyze the methodology used by I. Cretegny and S. J. Edelstein [(1993) J. Mol. Biol. 230, 733-738] to build a model of the fiber. Our examination reveals shortcomings in the methodology of Cretegny and Edelstein. One result of these shortcomings is that the model synthesized by Cretegny and Edelstein is not stereochemically acceptable because it gives rise to a large number of excessively close (less than 1.4 A) atom-atom contacts, suggesting interpenetration of the molecular envelopes.
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PMID:Analysis of the intermolecular contacts within sickle hemoglobin fibers: effect of site-specific substitutions, fiber pitch, and double-strand disorder. 800 79

Wobble rules for modified residues in the first anticodon position are derived. All known modifications are considered individually. Stereochemical analysis was made taking into account the interaction between the ribosomal A and P-site bound codon-anticodon duplexes. The wobble base-pair was considered as the right one if its formation did not lead to an uncompensated loss of hydrogen bonds or polar atom-ion bonds. From this requirement it follows that all modifications of U should restrict its translational specificity to purines (with the exception of xo5U, which should decode A, G and U). The restriction is carried out in a unified way: modifications inhibit the large propeller twist resulting from an increase of about 35 degrees in the torsion angle of the anticodon wobble base, interacting with the third codon base via a hydrogen-bonded water molecule. Such a twist is required to avoid a loss of the hydrogen bond of the bonded water molecule. The modifications in S2U, Se2U and Um should weaken their pairing with G, because they deform one of the two hydrogen bonds of the guanine NH2 group. G should be recognized by Se2U better than by S2U for the reason that the hydrogen bond Se...HN is weaker than the hydrogen bond S...HN. Among the modifications of C and G only that in k2C has a pronounced effect on wobble. The nucleoside k2C should pair only with A. The N-2 atom of k2C should be in the pyramidal state. The consequences following from the interduplex interaction are formulated. According to one of them, adenosine in the wobble position of the P-site tRNA should destabilize the A-site duplex. This can serve as an explanation for the fact that adenosine is very rarely observed in the anticodon wobble position.
J Mol Biol 1994 Jul 01
PMID:Analysis of action of wobble nucleoside modifications on codon-anticodon pairing within the ribosome. 802 43

Recent footprinting, sedimentation and neutron-scattering results obtained in vivo or on pre-translocation and post-translocation ribosomal complexes are integrated with cross-linking and immunoelectron microscopy information. It is proposed that the 30S subunit pulses during translocation and that its pre- and post-translocation structures are not necessarily identical. Accordingly, translocation is characterized by three consecutive conformational states of the 30S and 50S subunits. State 1 (the pre-translocation state) lasts until the elongation factor EF-G.GTP complex binds to the ribosome or adopts the GTPase conformation. State 2 (the translocation state, or the peak or plateau of the pulse) follows and lasts until EF-G adopts a subsequent conformation or is released from the ribosome. State 3 (the post-translocation state) ensues and lasts until A (aminoacyl) site binding of aminoacyl-tRNA. In state 2, 16S RNA hairpins 26 and 33-33A, located in the platform and the head of the 30S subunit, respectively, become kinked or twisted, and residue A1503, near the decoding site, becomes exposed. A platform twist is associated with P (peptide) to E (exit) site tRNA movements and a head twist with pivoting of the peptidyl-tRNA elbow from the A to the P site, around a (retractable?) S19 domain. These twists result in an unlocking of the platform and the head from the 50S subunit. Exposure of A1503 is tentatively associated with movements of mRNA or tRNA anticodon stem-loops. These twisted or otherwise-exposed residues readopt their previous setting upon completion of translocation, i.e. states 1 and 3 of 16S RNA differ more from state 2 than from each other.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Microbiol 1994 Mar
PMID:Structural dynamics of translating ribosomes: 16S ribosomal RNA bases that may move twice during translocation. 802 90


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