Reconciling MA'AT and molecular dynamics models of linkage conformation in oligosaccharides.
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ABSTRACT:
SUBMITTER: Meredith RJ
PROVIDER: S-EPMC8224179 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The RNA "GAGU" duplex, (5'GACGAGUGUCA)2, contains the internal loop (5'-GAGU-3')2 , which has two conformations in solution as determined by NMR spectroscopy. The major conformation has a loop structure consisting of trans-Watson-Crick/Hoogsteen GG pairs, A residues stacked on each other, U residues bulged outside the helix, and all sugars with a C2'-endo conformation. This differs markedly from the internal loops, (5'-GAGC-3')2, (5'-AAGU-3')2, and (5'-UAGG-3')2, which all have cis-Watson-Crick/Watson-Crick AG "imino" pairs flanked by cis-Watson-Crick/Watson-Crick canonical pairs resulting in maximal hydrogen bonding. Here, molecular dynamics was used to test whether the Amber force field (ff99 + bsc0 + OL3) approximates molecular interactions well enough to keep stable the unexpected conformation of the GAGU major duplex structure and the NMR structures of the duplexes containing (5'-GAGC-3')2, (5'-AAGU-3')2, and (5'-UAGG-3')2 internal loops. One-microsecond simulations were repeated four times for each of the duplexes starting in their NMR conformations. With the exception of (5'-UAGG-3')2, equivalent simulations were also run starting with alternative conformations. Results indicate that the Amber force field keeps the NMR conformations of the duplexes stable for at least 1 µsec. They also demonstrate an unexpected minor conformation for the (5'-GAGU-3')2 loop that is consistent with newly measured NMR spectra of duplexes with natural and modified nucleotides. Thus, unrestrained simulations led to the determination of the previously unknown minor conformation. The stability of the native (5'-GAGU-3')2 internal loop as compared to other loops can be explained by changes in hydrogen bonding and stacking as the flanking bases are changed.
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Project description:The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design.
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Project description:BACKGROUND: In the last decade, various coarse-grained elastic network models have been developed to study the large-scale motions of proteins and protein complexes where computer simulations using detailed all-atom models are not feasible. Among these models, the Gaussian Network Model (GNM) and Anisotropic Network Model (ANM) have been widely used. Both models have strengths and limitations. GNM can predict the relative magnitudes of protein fluctuations well, but due to its isotropy assumption, it can not be applied to predict the directions of the fluctuations. In contrast, ANM adds the ability to do the latter, but loses a significant amount of precision in the prediction of the magnitudes. RESULTS: In this article, we develop a single model, called generalized spring tensor model (STeM), that is able to predict well both the magnitudes and the directions of the fluctuations. Specifically, STeM performs equally well in B-factor predictions as GNM and has the ability to predict the directions of fluctuations as ANM. This is achieved by employing a physically more realistic potential, the Go-like potential. The potential, which is more sophisticated than that of either GNM or ANM, though adds complexity to the derivation process of the Hessian matrix (which fortunately has been done once for all and the MATLAB code is freely available electronically at http://www.cs.iastate.edu/~gsong/STeM), causes virtually no performance slowdown. CONCLUSIONS: Derived from a physically more realistic potential, STeM proves to be a natural solution in which advantages that used to exist in two separate models, namely GNM and ANM, are achieved in one single model. It thus lightens the burden to work with two separate models and to relate the modes of GNM with those of ANM at times. By examining the contributions of different interaction terms in the G? potential to the fluctuation dynamics, STeM reveals, (i) a physical explanation for why the distance-dependent, inverse distance square (i.e., 1/(r)2) spring constants perform better than the uniform ones, and (ii), the importance of three-body and four-body interactions to properly modeling protein dynamics.
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Project description:Members of the genus Bifidobacterium are common inhabitants of the gastrointestinal tract of humans and other mammals, where they ferment many diet-derived carbohydrates that cannot be digested by their host. To extend our understanding of bifidobacterial carbohydrate utilisation, we investigated the molecular mechanisms by which various strains of Bifidobacterium breve metabolize four distinct α-glucose and/or α-galactose-containing oligosaccharides, namely raffinose, stachyose, melibiose and melezitose. Here we demonstrate that all B. breve strains examined possess the ability to utilise raffinose, stachyose and melibiose. However, the ability to metabolize melezitose was not ubiquitous for all tested B. breve strains. Transcriptomic and functional genomic approaches identified a gene cluster dedicated to the metabolism of α-galactose-containing carbohydrates, while an adjacent gene cluster, dedicated to the metabolism of α-glucose-containing melezitose, was identified, yet being present only in those B. breve strains that were able to support growth on this carbohydrate. DNA-microarrays containing oligonucleotide primers representing each of the 1864 annotated genes on the genome of B. breve UCC2003 (O'Connell Motherway et al., 2011) were designed by and obtained from Agilent Technologies (Palo Alto, Ca., USA). Methods for cell disruption, RNA isolation, RNA quality control, complementary DNA synthesis and labeling were performed as described previously (Pokusaeva et al., 2009). Labeled cDNA was hybridized using the Agilent Gene Expression hybridization kit (part number 5188-5242) as described in the Agilent Two-Color Microarray-Based Gene Expression Analysis v4.0 manual (G4140-90050). Following hybridization, microarrays were washed in accordance with Agilent’s standard procedures and scanned using an Agilent DNA microarray scanner (model G2565A). Generated scans were converted to data files with Agilent's Feature Extraction software (Version 9.5). DNA-microarray data were processed as previously described (Garcia De La Nava et al., 2003). Differential expression tests were performed with the Cyber-T implementation of a variant of the t-test (Long et al., 2001). A gene was considered differentially expressed when p < 0.001 and an expression ratio of >3 or <0.33 relative to the control.
2013-08-16 | E-GEOD-47448 | biostudies-arrayexpress
Project description:Members of the genus Bifidobacterium are common inhabitants of the gastrointestinal tract of humans and other mammals, where they ferment many diet-derived carbohydrates that cannot be digested by their host. To extend our understanding of bifidobacterial carbohydrate utilisation, we investigated the molecular mechanisms by which various strains of Bifidobacterium breve metabolize four distinct α-glucose and/or α-galactose-containing oligosaccharides, namely raffinose, stachyose, melibiose and melezitose. Here we demonstrate that all B. breve strains examined possess the ability to utilise raffinose, stachyose and melibiose. However, the ability to metabolize melezitose was not ubiquitous for all tested B. breve strains. Transcriptomic and functional genomic approaches identified a gene cluster dedicated to the metabolism of α-galactose-containing carbohydrates, while an adjacent gene cluster, dedicated to the metabolism of α-glucose-containing melezitose, was identified, yet being present only in those B. breve strains that were able to support growth on this carbohydrate.
2013-08-16 | GSE47448 | GEO
Project description:Sulfated fucans from sea urchin egg jelly express well-defined chemical structures that vary with species. This species specificity regulates the sperm acrosome reaction, a critical step to assure intra-specific fertilization. In addition, these polysaccharides are involved in other biological activities such as anticoagulation. Although sulfation patterns are relevant to the levels of response in both activities, conformation and dynamics of these glycans are also contributing factors. However, data about these features of sulfated fucans are very rare. To address this, we have employed nuclear magnetic resonance experiments combined with molecular dynamics on structurally defined oligosaccharides derived from two sulfated fucans. The results have indicated that the oligosaccharides are flexible in solution. Ring conformation of their composing units displays just the (1)C4 chair configuration. In a particular octasaccharide, composed of two tetrasaccharide sequences, inter-residual hydrogen bonds play a role to decrease dynamics in these repeating units. Conversely, the linking disaccharide [-3)-α-L-Fucp-2(OSO3(-))-(1-3)-α-L-Fucp-4(OCO3(-))-(1-] located right between the two tetrasaccharide units has amplified motions suggested to be promoted by electrostatic repulsion of sulfates on opposite sides of the central glycosidic bond. This conjunction of information about conformation and dynamics of sulfated fucan oligosaccharides provides new insights to explain how these glycans behave free in solution and influenced by sulfation patterns. It may also serve for future studies concerning structure-function relationship of sulfated fucans, especially those involving sea urchin fertilization and anticoagulation.
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Project description:Oligosaccharide structures derived from the lipooligosaccharide of M. catarrhalis show that the highly branched glucose-rich inner core of the oligosaccharide has an altered conformation compared to the most truncated tetra-glucose-Kdo lgt1/4Δ oligosaccharide structure. Addition of one residue each to the (1-4) and (1-6) chains to give the lgt2Δ oligosaccharide is the minimum requirement for this conformational change to occur. Extensive molecular modeling and NMR investigations have shown that the (1-3), (1-4), and (1-6) glycosidic linkages from the central α-D-Glcp have significantly altered conformational preferences between the two structures. For the lgt1/4Δ oligosaccharide the (1-3) and (1-4) linkage populates predominantly the syn minimum on the conformational free energy map and for the (1-6) linkage conformational flexibility is observed, which is supported by 1H-NMR T1 measurements. For the lgt2Δ oligosaccharide the unusual "(1-4)anti-ψ(1-6)gg" conformation, which could be confirmed by long-range NOE signals, is a dominant conformation in which the oligosaccharide is very compact with the terminal α-D-GlcNAc residue folding back towards the center of the molecule leading to an extensive intra-molecular hydrophobic interaction between the terminal residues. Comparing effective H-H distances, which were calculated for conformational sub-ensembles, with the NOE distances revealed that typically multiple conformations could be present without significantly violating the measured NOE restraints. For lgt2Δ the presence of more than one conformation is supported by the NOE data.
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Project description:This work presents the analysis of the conformation of albumin in the temperature range of 300 K - 312 K , i.e., in the physiological range. Using molecular dynamics simulations, we calculate values of the backbone and dihedral angles for this molecule. We analyze the global dynamic properties of albumin treated as a chain. In this range of temperature, we study parameters of the molecule and the conformational entropy derived from two angles that reflect global dynamics in the conformational space. A thorough rationalization, based on the scaling theory, for the subdiffusion Flory-De Gennes type exponent of 0 . 4 unfolds in conjunction with picking up the most appreciable fluctuations of the corresponding statistical-test parameter. These fluctuations coincide adequately with entropy fluctuations, namely the oscillations out of thermodynamic equilibrium. Using Fisher's test, we investigate the conformational entropy over time and suggest its oscillatory properties in the corresponding time domain. Using the Kruscal-Wallis test, we also analyze differences between the root mean square displacement of a molecule at various temperatures. Here we show that its values in the range of 306 K - 309 K are different than in another temperature. Using the Kullback-Leibler theory, we investigate differences between the distribution of the root mean square displacement for each temperature and time window.
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Project description:Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo-blood group antigens at a secondary binding site. Herein, we studied the conformational dynamics of Lewis Y (LeY) oligosaccharides, H-tetrasaccharides and A-pentasaccharides, in aqueous solution by conducting accelerated molecular dynamics (aMD) simulations. The flexible nature of both oligosaccharides was displayed in aMD simulations. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, 4C1 and 1C4 puckers were sampled for all but GalNAc monosaccharides, while either the 4C1 (GlcNAc, Gal, GalNAc) or 1C4 (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. In aMD, the complete transition from the 4C1 to 1C4 pucker was sampled for GlcNAc and Gal in both oligosaccharides. Further, we have observed a transition from the open to closed conformer in the case of A-pentasaccharide, while H-tetrasaccharide remains in the open conformation throughout the simulation. Both oligosaccharides adopted an open conformation in the CT binding site. Moreover, we have investigated the molecular basis of recognition of LeY oligosaccharides by the B subunit of the cholera toxin of classical and El Tor biotypes using the molecular mechanics generalized Born surface area (MM/GBSA) scheme. The O blood group determinant, H-tetrasaccharide, exhibits a stronger affinity to both biotypes compared to the A blood group determinant, A-pentasaccharide, which agrees with the experimental data. The difference in binding free energy between O and A blood group determinants mainly arises due to the increased entropic cost and desolvation energy in the case of A-pentasaccharide compared to that of H-tetrasaccharide. Our study also reveals that the terminal Fuc3 contributes most to the binding free energy compared to other carbohydrate residues as it forms multiple hydrogen bonds with CT. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin.
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