Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Conformational accessibility”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed2006

Prediction of atomic structure from sequence for double helical DNA oligomers.

DNA can adopt different conformations depending on the base sequence, solvent, electrolyte composition and concentration, pH, temperature, and interaction with proteins. Here we present a model for calculating the three-dimensional atomic structure of double-stranded DNA oligomers. A theoretical energy function is used for calculating the interactions within the base steps and an empirical backbone function is used to restrict the conformational space accessible to the bases and to account for the conformational coupling of neighboring steps in a sequence. Conformational searching on large structures or a large number of structures is possible, because each base step can be described by just two primary degrees of freedom (slide and shift). A genetic algorithm is used to search for low-energy structures in slide-shift space, and this allows very rapid optimization of DNA oligomers. The other base step parameters have been previously optimized for all possible slide-shift sequence combinations, and a heuristic algorithm is used to add the atomic details of the backbone conformation in the final step of the calculation. The structures obtained by this method are very similar to the corresponding X-ray crystal structures observed experimentally. The average RMSD is 2.24 Angstroms for a set of 20 oligomer structures. For 15 of these sequences, the X-ray crystal structure is the global energy minimum. The other 5 are bistable sequences that have B-form global energy minima but crystallize as A-DNA.

Algorithms↗
PubMed1999

Structural, Conformational, and Spectroscopic Studies of Primary Amine Complexes of Iron(II) Porphyrins.

Three novel bis(primary amine)iron(II) porphyrins [Fe(TPP)(RNH(2))(2)], where RNH(2) = 1-butylamine, benzylamine, and phenethylamine, have been synthesized and characterized by X-ray crystallography and IR, electronic, and Mössbauer spectroscopy. The compounds provide unprecedented structural data for the coordination of primary amines by iron(II) porphyrins. The Fe-N(ax) distances of [Fe(TPP)(1-BuNH(2))(2)], [Fe(TPP)(BzNH(2))(2)], and [Fe(TPP)(PhCH(2)CH(2)NH(2))(2)] are 2.039(3), 2.043(3), and 2.028(2) Å, respectively. The Fe-N(p) distances of the three complexes average 1.990(2) Å. The zero-field Mössbauer spectra (5-300 K) show comparable isomer shifts (0.393(1)-0.493(1) mm/s) and quadrupole splittings (1.144(6)-1.204(3) mm/s) that are consistent with an S = 0 iron(II) assignment in each case. The bis(primary amine) complexes are structurally and spectroscopically similar to [Fe(TPP)(Py)(2)] derivatives, where Py = an unsubstituted pyridine. Molecular mechanics (MM) calculations with a force field parametrized for primary and secondary amine complexes of iron(II) porphyrins show that stable conformations arise when the alpha-CH(2) and NH(2) protons of the coordinated ligands are staggered relative to the Fe-N(p) bonds of the porphyrin core. The lowest energy conformations of the three [Fe(TPP)(RNH(2))(2)] complexes therefore have the ligand alpha-carbons positioned directly over the Fe-N(p) bonds of the porphyrin core. The X-ray structure of [Fe(TPP)(PhCH(2)CH(2)NH(2))(2)] lies close to the global minimum (phi(1), phi(2) = 0, 180 degrees ) on the potential surface, while [Fe(TPP)(BzNH(2))(2)] and [Fe(TPP)(1-BuNH(2))(2)] show deviations that may be attributed to packing interactions in the solid and intrinsically low barriers to axial ligand rotation (<0.5 kcal/mol). Three types of minimum energy conformation are accessible for [Fe(TPP)(Pip)(2)]. The lowest energy conformation has an S(4)-ruffled porphyrin core. The conformation which matches the X-ray structure (Radonovich, L. J.; Bloom, A.; Hoard, J. L. J. Am. Chem. Soc. 1972, 94, 2073-2078) is a local minimum (1.6 kcal/mol higher in energy than the global minimum) with exact inversion symmetry. Higher in vacuo strain energy barriers ( approximately 2.2 kcal/mol) separate the potential minima of [Fe(TPP)(Pip)(2)], consistent with the increased bulk of the secondary amine axial ligands.

Journal Article↗
PubMed1992

Conformation/activity studies of rationally designed potent anti-adhesive RGD peptides.

The Arg-Gly-Asp (RGD) sequence is a universal cell-recognition site of various extracellular proteins that interact with integrin cell-surface receptors. In order to design low-molecular-mass RGD protein antagonists, the determination of the biologically active conformation is a prerequisite. We present a method that yields detailed insight into the steric factors which govern the binding of the ligands to their receptors by systematically scanning the conformational space accessible for the tripeptide sequence RGD. The investigation is based on the conformationally controlled design of homodetic cyclic oligopeptides and their structural determination, coupled with biological assays. For this purpose, a whole set of cyclic pentapeptides and hexapeptides has been synthesized and their three-dimensional structures in solution analyzed by modern two-dimensional NMR techniques in combination with restrained and free molecular dynamics simulations. Their biological activity was compared with that of linear GRGDS in inhibition assays of tumor cell adhesion to laminin P1 and vitronectin substrates. An up to 100-fold, and in part selective, increase in activity was observed for two cyclic pentapeptides. Most other peptides showed a decreased activity which, however, was useful to correlate activity with rather small variations in conformation. Detailed comparative studies of the systematically designed conformations and the corresponding anti-adhesive activities offer an access to lead structures for a rational indirect drug design of peptide and peptidomimetic pharmaceuticals with strong interfering activity for integrin-mediated cell-cell and cell-matrix interactions.

Amino Acid Sequence↗
PubMed1992

The utility of side-chain cyclization in determining the receptor-bound conformation of peptides: cyclic tripeptides and angiotensin II.

The effect of side-chain cyclization on accessible backbone conformations of tripeptides, X-Ala-Y (X and/or Y = Cys, Hcy (Hcy: homocysteine), cis 4-mercaptoproline (MPc), and trans 4-mercaptoproline (MPt)), was elucidated using two variants of systematic conformational search. In addition to cyclization through a disulfide bond, the thioether (-S-CH2-) and amide (-CO-NH-) side-chain analogues of Cys-Ala-Cys and Hcy-Ala-Hcy were evaluated. The number of valid backbone conformations and the allowed phi, psi space were evaluated for each compound, and the ability of the cyclic tripeptides to accommodate beta-turn conformations was examined in order to assess the value of cyclization in limiting conformational freedom. Based on the number of conformations, cyclization was highly effective in reducing the backbone degree of freedom: in order of decreasing number of conformations, Ala-Ala-Ala 1 >> Hcy-Ala-Hcy 2 >> Cys-Ala-Hcy 3 approximately equal to Hcy-Ala-Cys 4 >> MPc-Ala-Hcy 5, 7 > Cys-Ala-Cys 6 > MPc-Ala-Cys 8 > Hcy-Ala-MPt 9 > Cys-Ala-MPt 10 approximately equal to MPc-Ala-MPt 11. Although Hcy-Ala-Hcy 2 had the greatest number of conformations of the cyclic peptides studied, it was still greatly constrained relative to its linear analogue 1. The bicyclic ring system introduced by MP was even more effective in constraining the cycle, having greater impact at position 3 than at position 1. Under the conditions of the study, cyclization of MP-containing analogues could be effected only with the cis isomer (MPc) at position 1 and/or the trans isomer (MPt) at position 3. Sterically allowed conformations of Ala2 for the cyclic tripeptides 2-4 were generally similar to those of the linear tripeptide 1, while those of Cys-Ala-Cys 6 and MPc-Ala-Hcy 7 were restricted to a smaller region of phi 2, psi 2 space: the right- and left-handed alpha-helical conformation and the beta-conformation. This trend was even more pronounced for Hcy-Ala-MPt 9, Cys-Ala-MPt 10, and MPc-Ala-MPt 11, in which Ala2 was severely restricted to a very small region of phi, psi space: the left-handed alpha-helical conformation for 9-11, plus the beta conformation for 9. This suggests that MP at the 3-position is incompatible with a right-handed alpha-helical conformation at position 2.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1990

Structural elements pertinent to the interaction of cyclosporin A with its specific receptor protein, cyclophilin.

Cyclophilin (163 amino acids; 17,737 daltons) is a ubiquitous cytosolic protein that specifically binds the potent immunosuppressive drug cyclosporin A (CsA). To characterize the structural details of this interaction, extensive use has been made of two-dimensional (2D) NMR methods. For studies on CsA, these methods are being used to assign the conformational space accessible to CsA by analysis of the spectra from the multiple CsA conformers present in slow exchange in mixed solvent systems. These same 2D NMR methods also have been used for extensive studies of the major bovine thymus cyclophilin (CyP) isoform and its complex with stoichiometric amounts of CsA. In the former case, these studies have revealed 81% of the 156 expected HN-H alpha crosspeaks. The complete spin-coupled spin systems for one-third of these amide resonances have been assigned according to amino acid type. After exhaustive D2O exchange, there remain 44 amide protons which exhibit 2D NMR features indicative of a hydrophobic domain with beta-sheet secondary structure. The CsA-complexed form of CyP exhibits a discrete structure and set of resonances in slow exchange with the drug-free CyP. The amino acids that have been specifically identified to be affected by the interaction are limited in number and include three Phe residues, the unique Trp at position 120, and two Ala residues.

Amino Acid Sequence↗
PubMed1990

Design of biologically active, conformationally constrained GnRH antagonists.

The introduction of conformational constraints into a flexible peptide hormone can be exploited to develop models for the conformation required for receptor binding and activity. In this review, we illustrate this approach to analog design using our work on antagonists of gonadotropin-releasing hormone (GnRH). Design of a conformationally constrained, competitive antagonist of GnRH, cyclo[delta 3,4 Pro-D4ClPhe-DTrp-Ser-Tyr-DTrp-NMeLeu-Arg-Pro-bet a Ala] led to the prediction of its bioactive conformation. Template forcing experiments show that this conformation is accessible to other active GnRH analogs. Two-dimensional NMR studies verified the predicted conformation in solution. The predicted binding conformation has recently been used to design two new analogs incorporating side chain-side chain linkages suggested by the conformational model: Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-DTrp-Leu-Arg-Asp-Gly- NH2 and Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-D2Nal-Leu-Arg-Pro-Asp -NH2. These analogs were synthesized and the one predicted to be most similar to the parent conformation had equivalent potency while the second, designed to refine the conformational hypothesis, was found to exhibit enhanced potency, thus confirming the original binding conformation hypothesis. These compounds and their derivatives now provide a new class of GnRH antagonists possessing both high biological potency and limited conformational flexibility, thus making them ideal for both biophysical and structure-activity studies.

Amino Acid Sequence↗
PubMed2003

Highly diastereoselective hydrogenations leading to beta-hydroxy delta-lactones in hydroxy-protected form. A modified view of delta-lactone conformations.

Enol MEM ethers 4 and 15 and the corresponding enol acetates were hydrogenated over Pd/C with very high (>99%) diastereoselectivity to saturated delta-lactones. A stereochemical generalization can be formulated thus: trans-5,6-disubstituted 1-oxa-3-cyclohexen-2-ones (e.g. 14 and 15) are hydrogenated over Pd with high selectivity from the side trans to the C(6)-substituent. A mechanistic rationalization of the stereochemical outcome in the Pd-catalyzed hydrogenation of this as well as other types of substituted alpha,beta-unsaturated delta-lactones is presented. An analysis of X-ray crystallographic data for 67 compounds demonstrated a great conformational diversity of the saturated delta-lactone ring. Besides, ab initio calculations (HF/6-31G) indicated a very high conformational mobility. Thus, the lowest calculated transition state for the conversion of the half-chair, most stable, conformer of delta-valerolactone to the boat-type conformer lies only 1.93 kcal/mol above the former. Beside these two conformers, also chair, envelope and skew conformations are accessible; all lie less than 2 kcal/mol above the half-chair. The previous conformational paradigm comprising only boat and half-chair types is incomplete.

Catalysis↗
PubMed1992

Immunoglobulin heavy-chain and CD3 delta-chain gene enhancers are DNase I-hypersensitive in hemopoietic progenitor cells.

Multipotential interleukin 3-dependent non-immortalized murine hemopoietic progenitor cells have DNase I-hypersensitive sites in the immunoglobulin heavy-chain and CD3 delta enhancers and transcribe germ-line T-cell antigen receptor gamma-chain (TCR gamma), but not IgM or TCR beta, genes. Induction of myeloid differentiation in these cells clones down expression and/or transcriptional accessibility of the immunoglobulin heavy-chain and TCR gamma genes. The CD3 delta enhancer region remains DNase I-hypersensitive but closes down in B cells. In embryonic stem cells and pan-mesodermal cells, these genes or enhancer regions are neither expressed nor DNase I-hypersensitive. These data suggest that lineage potential may be programmed, at least in part, by alterations in the accessibility or conformation of regulatory regions of genes and that some promiscuity of gene expression and/or accessibility can precede lineage commitment and maturation in progenitor cells induced to self-renew by interleukin 3.

Animals↗
PubMed2025

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Journal Article↗
PubMed1998

Are knowledge-based potentials derived from protein structure sets discriminative with respect to amino acid types?

The parametric description of residue environments through solvent accessibility, backbone conformation, or pairwise residue-residue distances is the key to the comparison between amino acid types at protein sequence positions and residue locations in structural templates (condition of protein sequence-structure match). For the first time, the research results presented in this study clarify and allow to quantify, on a rigorous statistical basis, to what extent the amino acid type-specific distributions of commonly used environment parameters are discriminative with respect to the 20 amino acid types. Relying on the Bahadur theory, we estimate the probability of error in a single-sequence-structure alignment based on weak or absent discriminative power in a learning database of protein structure. We present the results for many residue environment variables and demonstrate that each fold description parameter is sensitive with respect to only a few amino acid types while indifferent to most of the other amino acid types. Even complex structural characteristics combining solvent-accessible surface area, backbone conformation, and pairwise distances distinguish only some amino acid types, whereas the others remain nondiscriminated. We find that the knowledge-based potentials currently in use treat especially Ala, Asp, Gln, His, Ser, Thr, and Tyr as essentially "average" amino acids. Thus, highly discriminative amino acid types define the alignment register in gapless sequence-structure alignments. The introduction of gaps leads to alignment ambiguities at sequence positions occupied by nondiscriminated amino acid types. Therefore, local sequence-structure alignments produced by techniques with gaps cannot be reliable. Conceptionally new and more sensitive environment parameters must be invented.

Amino Acids↗
PubMed1999

Conformational change of ascidiacyclamide caused by asymmetric modification for an isoleucine residue: structural analyses of [Gly], [Leu], and [Phe]ascidiacyclamides by x-ray diffraction and NMR spectroscopy.

Ascidiacyclamide, a cytotoxic cyclic peptide from tunicate, is composed of unusual amino acids and has a repeated sequence, c[-thiazole-D-Val-oxazoline-L-Ile-]2 ([Ile]ASC). The symmetric chemical structure has been assumed to be correlated with the cytotoxicity, and it is reasonable to consider that the disturbance of its structure from the C2 symmetry results in the changes of conformation and activity. In order to quantitatively estimate the molecular conformation-activity relationship, an isoleucine residue was substituted by Gly, Leu, or Phe to disturb the C2 symmetry. The conformations of three derivatives were examined by nmr spectroscopy and the crystal structure of [Leu]ASC was also analyzed by x-ray diffraction method. The 1H-nmr experiments and the constrained molecular dynamics simulations showed the twisted "figure 8" conformers for [Gly] and [Phe]ASCs and the "square" conformer for [Leu]ASC in the DMSO solution. The x-ray crystal analysis of [Leu]ASC also revealed the square form similar to the solution structure. On the other hand, their cytotoxic activities were measured using L1210 leukemia cells and were related with the bulkiness and/or hydrophobicity of the side chain of the substituted amino acid; [Phe] > or = [Ile] > [Leu] >> [Gly]ASCs. As an attempt to consider the correlation between the activity and conformer, the accessible surface area (ASA) was calculated for each derivative to estimate the size or bulkiness of its conformation. Although the ASAs of nmr structures were not directly related to the type of conformer (figure 8 or square form), it was an important probe to consider the cytotoxicity of each derivative.

Amino Acid Substitution↗
PubMed2001

Methods of peptide conformation studies.

In solution most of the peptides assume multiple flexible conformations. Determination of the dominant conformers and evaluation of their populations is the aim of peptide conformation studies, in which theoretical and experimental methods play complementary roles. Molecular dynamics or Monte Carlo methods are quite effective in searching the conformational space accessible to a peptide but they are not able to estimate, precisely enough, the populations of various conformations. Therefore, they must be supplemented by experimental data. In this paper, a short review of the experimental methods, most widely used in peptide conformational studies, is presented. Among them NMR plays the leading role. Valuable information is also obtained from hydrogen exchange, fluorescence resonance energy transfer, and circular dichroism measurements. The advantages and shortcomings of these methods are discussed.

Circular Dichroism↗
PubMed1995

Magnesium acetate induces a conformational change in Escherichia coli primase.

Primase from Escherichia coli is a single-stranded DNA-dependent RNA polymerase. As such, it requires magnesium to carry out catalysis. Limited tryptic digestion was used to probe the conformations of primase as a function of magnesium acetate concentration. In the absence of magnesium, trypsin cleaved primase at three sites. Magnesium acetate induced a conformational change such that one of these sites became inaccessible to trypsin digestion and a new site became trypsin accessible. The conformational change was only induced by Mg(OAc)2 and not MnCl2, CaCl2, NaOAc or LiCl, indicating a clear magnesium acetate-dependent conformational change. The effect was slightly induced by MgSO4 and MgCl2. An allosteric binding model indicates that primase binds at least two magnesiums in a cooperative manner. The data were best fit to a two-state model in which one conformation had a high affinity for magnesium, KR = 83.4 M-1, and the other state had virtually no affinity.

Acetates↗
PubMed2006

Structure of the 21-30 fragment of amyloid beta-protein.

Folding and self-assembly of the 42-residue amyloid beta-protein (Abeta) are linked to Alzheimer's disease (AD). The 21-30 region of Abeta, Abeta(21-30), is resistant to proteolysis and is believed to nucleate the folding of full-length Abeta. The conformational space accessible to the Abeta(21-30) peptide is investigated by using replica exchange molecular dynamics simulations in explicit solvent. Conformations belonging to the global free energy minimum (the "native" state) from simulation are in good agreement with reported NMR structures. These conformations possess a bend motif spanning the central residues V24-K28. This bend is stabilized by a network of hydrogen bonds involving the side chain of residue D23 and the amide hydrogens of adjacent residues G25, S26, N27, and K28, as well as by a salt bridge formed between side chains of K28 and E22. The non-native states of this peptide are compact and retain a native-like bend topology. The persistence of structure in the denatured state may account for the resistance of this peptide to protease degradation and aggregation, even at elevated temperatures.

Amyloid beta-Peptides↗
PubMed1985

Dynamics and conformational energetics of a peptide hormone: vasopressin.

A theoretical methodology for use in conjunction with experiment was applied to the neurohypophyseal hormone lysine vasopressin for elucidation of its accessible molecular conformations and associated flexibility, conformational transitions, and dynamics. Molecular dynamics and energy minimization techniques make possible a description of the conformational properties of a peptide in terms of the precise positions of atoms, their fluctuations in time, and the interatomic forces acting on them. Analysis of the dynamic trajectory of lysine vasopressin shows the ability of a flexible peptide hormone to undergo spontaneous conformational transitions. The excursions of an individual phenylalanine residue exemplify the dynamic flexibility and multiple conformational states available to small peptide hormones and their component residues, even within constraints imposed by a cyclic hexapeptide ring.

Chemical Phenomena↗
PubMed1989

Comparative X-ray and Fourier-transform-infrared investigations of conformational properties of bacterial and synthetic lipid A of Escherichia coli and Salmonella minnesota as well as partial structures and analogues thereof.

By using the X-ray and infrared spectroscopic characteristics of various synthetic analogues and partial structures of lipid A in the dried state, a comparison of these compounds with their natural counterparts was undertaken. As judged by their X-ray diffraction and infrared spectroscopic features, the compounds tested could be divided into two main groups. The first group covered those samples synthesized in accordance with a previously assumed structure, while those synthesized in accordance with present knowledge on the lipid-A primary structure formed the second group. Members of the first group were characterized by a liquid-like, alpha-type arrangement of their fatty acyl chains in a non-lamellar supramolecular structure, while all members of the second group formed bilayered phases with a much more ordered, beta-type conformation of their fatty acyl chains. Synthetic Escherichia coli-type lipid A (compound 506), proved to be essentially identical to its natural counterpart with respect to those conformational properties accessible by our methods. The synthetic hepta-acyl species of Salmonella minnesota lipid A (compound 516) revealed an unexpected conformational behaviour, whereby a fatty-acyl-chain packing could be detected which was different from the hexagonal arrangement found for all other compounds of the second group.

Escherichia coli↗
PubMed2006

Shape persistence and bistability of planar three-fold core polyphenylene dendrimers: a molecular dynamics study.

We present an atomistic molecular dynamics investigation of the structural time evolution of isolated polyphenylene dendrimers, carbon based dendrimers with a planar core formed by a 1,3,5 trisubstituted benzene ring. Simulations are carried out at low (80 K) and room temperature. A general classification of the conformations (core conformations) assumed by the three dendrimer branches with respect to the planar core is presented. It is found that out of the six possible core conformations only four are stable, the remaining two being unstable for steric reasons. For second generation dendrimers, two of the four accessible core conformations are associated with an open arrangement of the three branches attached to the planar 3-fold core of the dendrimer, whereas the remaining two are associated with a collapsed arrangement of two branches. At low temperature the initial conformation is generally conserved whereas at room temperature jumps among the four possible core conformations are observed in the nanosecond time range. For second generation dendrimers the core conformation jumps are associated with an oscillation between two global shape states: open and collapsed. The computed bistability of the global shape suggests additional possible functional uses for some of these carbon based dendrimers.

Journal Article↗
PubMed2002

Molecular dynamics simulations of alpha2 --> 8-linked disialoside: conformational analysis and implications for binding to proteins.

Computational methods have played a key role in elucidating the various three-dimensional structures of oligosaccharides. Such structural information, together with other experimental data, leads to a better understanding of the role of oligosaccharide in various biological processes. The disialoside Neu5Ac-alpha2-->8-Neu5Ac appears as the terminal glycan in glycoproteins and glycolipids, and is known to play an important role in various events of cellular communication. Neurotoxins such as botulinum and tetanus require Neu5Ac-alpha2 --> 8-Neu5Ac for infecting the host. Glycoconjugates containing this disialoside and the enzymes catalyzing their biosynthesis are also regulated during cell growth, development, and differentiation. Unlike other biologically relevant disaccharides that have only two linkage bonds, the alpha2-->8-linked disialoside has four: C2-O, O-C8', C8'-C7', and C7'-C6'. The present report describes the results from nine 1 ns MD simulations of alpha2-->8-linked disialoside (Neu5Ac-alpha2-->8-Neu5Ac); simulations were run using GROMOS96 by explicitly considering the solvent molecules. Conformations around the O-C8' bond are restricted to the +sc/+ap regions due to stereochemical reasons. In contrast, conformations around the C2-O and C8'-C7' bonds were found to be largely unrestricted and all the three staggered regions are accessible. The conformations around the C7'-C6' bond were found to be in either the -sc or the anti region. These results are in excellent agreement with the available NMR and potential energy calculation studies. Overall, the disaccharide is flexible and adopts mainly two ensembles of conformations differing in the conformation around the C7'-C6' bond. The flexibility associated with this disaccharide allows for better optimization of intermolecular contacts while binding to proteins and this may partially compensate for the loss of conformational entropy that may be incurred due to disaccharide's flexibility.

Algorithms↗