Publications by authors named "Michelle M Kuttel"

22 Publications

  • Page 1 of 1

Conformational and Immunogenicity Studies of the Serogroup 6 O-Antigen: The Effect of O-Acetylation.

Vaccines (Basel) 2021 Apr 27;9(5). Epub 2021 Apr 27.

Department of Computer Science, University of Cape Town, Rondebosch 7701, South Africa.

The pathogenic bacterium is a leading cause of diarrheal disease and mortality, disproportionately affecting young children in low-income countries. The increasing prevalence of antibiotic resistance in necessitates an effective vaccine, for which the bacterial lipopolysaccharide O-antigen is the primary target. serotype 6 has been proposed as a multivalent vaccine component to ensure broad protection against . We have previously explored the conformations of O-antigens from serogroups Y, 2, 3, and 5 that share a common saccharide backbone (serotype Y). Here we consider serogroup 6, which is of particular interest because of an altered backbone repeat unit with non-stoichiometric O-acetylation, the antigenic and immunogenic importance of which have yet to be established. Our simulations show significant conformational changes in serogroup 6 relative to the serotype Y backbone. We further find that O-acetylation has little effect on conformation and hence may not be essential for the antigenicity of serotype 6. This is corroborated by an in vivo study in mice, using Generalized Modules for Membrane Antigens (GMMA) as O-antigen delivery systems, that shows that O-acetylation does not have an impact on the immune response elicited by the serotype 6 O-antigen.
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http://dx.doi.org/10.3390/vaccines9050432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144980PMC
April 2021

Molecular modeling provides insights into the loading of sialic acid-containing antigens onto CRM: the role of chain flexibility in conjugation efficiency and glycoconjugate architecture.

Glycoconj J 2021 Mar 15. Epub 2021 Mar 15.

Department of Chemistry, University of Cape Town, 7701, Cape Town, South Africa.

Vaccination is the most cost-effective way to control disease caused by encapsulated bacteria; the capsular polysaccharide (CPS) is the primary virulence factor and vaccine target. Neisseria meningitidis (Nm) serogroups B, C, Y and W all contain sialic acid, a common surface feature of human pathogens. Two protein-based vaccines against serogroup B infection are available for human use while four tetravalent conjugate vaccines including serogroups C, W and Y have been licensed. The tetravalent Menveo® conjugate vaccine is well-defined: a simple monomeric structure of oligosaccharides terminally conjugated to amino groups of the carrier protein CRM. However, not only is there a surprisingly low limit for antigen chain attachment to CRM, but different serogroup saccharides have consistently different CRM loading, the reasons for which are unclear. Understanding this phenomenon is important for the long-term goal of controlling conjugation to prepare conjugate vaccines of optimal immunogenicity. Here we use molecular modeling to explore whether antigen flexibility can explain the varying antigen loading of the conjugates. Because flexibility is difficult to separate from other structural factors, we focus on sialic-acid containing CPS present in current glycoconjugate vaccines: serogroups NmC, NmW and NmY. Our simulations reveal a correlation between Nm antigen flexibility (NmW > NmC > NmY) and the number of chains attached to CRM, suggesting that increased flexibility enables accommodation of additional chains on the protein surface. Further, in silico models of the glycoconjugates confirm the relatively large hydrodynamic size of the saccharide chains and indicate steric constraints to further conjugation.
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http://dx.doi.org/10.1007/s10719-021-09991-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957279PMC
March 2021

Molecular Modeling of the Serogroup 3 and 5 O-Antigens and Conformational Relationships for a Vaccine Containing Serotypes 2a and 3a.

Vaccines (Basel) 2020 Nov 2;8(4). Epub 2020 Nov 2.

Department of Computer Science, University of Cape Town, Rondebosch 7701, South Africa.

The pathogenic bacterium is a leading global cause of diarrheal disease. The O-antigen is the primary vaccine target and distinguishes the 30 serotypes reported. Except for serotype 6, all serotypes have a common backbone repeating unit (serotype Y), with variations in substitution creating the various serotypes. A quadrivalent vaccine containing serotypes 2a and 3a (as well as 6 and ) is proposed to provide broad protection against non-vaccine serotypes through shared epitopes and conformations. Here we model the O-antigen (O-Ag) conformations of serogroups 3 and 5: a continuation of our ongoing systematic study of the O-antigens that began with serogroup 2. Our simulations show that serogroups 2, 3, and 5 all have flexible O-Ags, with substitutions of the backbone altering the chain conformations in different ways. Our analysis suggests three general heuristics for the effects of substitution on the O-Ag conformations: (1) substitution on rhamnose C reduces the extension of the O-Ag chain; (2) substitution at O-3 of rhamnose A restricts the O-Ags to predominantly helical conformations, (3) substitution at O-3 of rhamnose B has only a slight effect on conformation. The common O-Ag conformations across serotypes identified in this work support the assumption that a quadrivalent vaccine containing serotypes 2a and 3a could provide coverage against serotype 3b and serogroup 5.
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http://dx.doi.org/10.3390/vaccines8040643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712985PMC
November 2020

Mechanistic Study of Potent Fluorinated EGFR Kinase Inhibitors with a Quinazoline Scaffold against L858R/T790M/C797S Resistance Mutation: Unveiling the Fluorine Substituent Cooperativity Effect on the Inhibitory Activity.

J Phys Chem B 2020 07 30;124(28):5813-5824. Epub 2020 Jun 30.

Department of Computer Science, University of Cape Town, Cape Town 7701, South Africa.

Fluorination has considerable potential with regard to the design of kinase inhibitors for anticarcinoma therapy. It was recently reported that fluorination increases the potency of inhibitors of the epidermal growth factor receptor (EGFR), mutations of which have been linked specifically to nonsmall-cell lung cancer. For the L858R/T790M/C797S triplet mutant (EGFR), a difluorinated inhibitor, , was found to have 4.23 times greater potency against the EGFR than an unfluorinated inhibitor, . This discovery necessitates a rational explanation for the underlying inhibitory mechanisms. Here, we apply multiple computational approaches to explore, validate, and differentiate the binding modes of and in the EGFR and investigate the cooperativity effect of fluorine substituents on the inhibitory activity. Our results showed that the EGFR in the presence of undergoes a series of conformational changes that favor inhibitor binding to both the active and allosteric sites. Further, the cooperativity effect of fluorine substituents is positive: the complex stability is increased by each additional fluorine substituent. Estimated binding free energies show good correlation with the experimental biological activity. Subsequently, the decomposition energy analysis revealed that the van der Waals interaction is the principal force contributing to variations in the binding affinities of and to the EGFR. Per-residue energy-based hierarchical clustering analysis suggests that three hot-spot residues, L718, K745, and D855, are the key in achieving optimal binding modes for with higher affinity in the EGFR compared to . This study provides a rationale for the superior EGFR-inhibitory potency exhibited by over , which is expected to be useful for the future rational structure-based design of novel EGFR inhibitors with improved potency and selectivity.
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http://dx.doi.org/10.1021/acs.jpcb.0c03440DOI Listing
July 2020

Capsular GXM Conformation and Epitope Presentation: A Molecular Modelling Study.

Molecules 2020 Jun 7;25(11). Epub 2020 Jun 7.

Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.

The pathogenic encapsulated fungus causes serious disease in immunosuppressed hosts. The capsule, a key virulence factor, consists primarily of the glucuronoxylomannan polysaccharide (GXM) that varies in composition according to serotype. While GXM is a potential vaccine target, vaccine development has been confounded by the existence of epitopes that elicit non-protective antibodies. Although there is evidence for protective antibodies binding conformational epitopes, the secondary structure of GXM remains an unsolved problem. Here an array of molecular dynamics simulations reveal that the GXM mannan backbone is consistently extended and relatively inflexible in both serotypes A and D. Backbone substitution does not alter the secondary structure, but rather adds structural motifs: β DGlcA and β DXyl side chains decorate the mannan backbone in two hydrophillic fringes, with mannose-6-O-acetylation forming a hydrophobic ridge between them. This work provides mechanistic rationales for clinical observations-the importance of O-acetylation for antibody binding; the lack of binding of protective antibodies to short GXM fragments; the existence of epitopes that elicit non-protective antibodies; and the self-aggregation of GXM chains-indicating that molecular modelling can play a role in the rational design of conjugate vaccines.
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http://dx.doi.org/10.3390/molecules25112651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321252PMC
June 2020

Effects of Glucosylation and O-Acetylation on the Conformation of Serogroup 2 O-Antigen Vaccine Targets.

J Phys Chem B 2020 04 31;124(14):2806-2814. Epub 2020 Mar 31.

Department of Computer Science, University of Cape Town, Rondebosch 7701, South Africa.

Shigellosis is an enteric disease with high morbidity and mortality, particularly in developing countries. There is currently no licensed vaccine available. Most infection is caused by , of which 30 serotypes have been recognized based on O-antigen polysaccharide structure. Almost all serotypes share the same repeating unit backbone (serotype Y), with varying glucosylation, O-acetylation and phosphorylation. The O-antigen is the primary vaccine target; the vaccine valency (and hence cost) can be reduced by cross-protection. Our planned systematic conformational study of starts here with 2a, the dominant cause of infection globally. We employ microsecond molecular dynamics simulations to compare the conformation of the unsubstituted serotype Y backbone with the serogroup 2 O-antigens, to investigate the effect of glucosylation and O-acetylation (O-factor 9) on conformation. We find that serotype Y is highly flexible, whereas glucosylation in 2a restricts flexibility and induces C-curve conformations. Further, the glucose side-chains adopt two distinct conformations, corroborated by the antibody-bound crystal structure data. Additional substitution on O-3 of rhamnose A (whether O-acetylation in 2a or glucosylation in 2b) induces helical conformations. Our results suggest that the O-3-acetylated 2a antigen will elicit cross-protection against 2b, as well as other serotypes containing O-factor 9.
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http://dx.doi.org/10.1021/acs.jpcb.0c01595DOI Listing
April 2020

Modeling the conformations of Neisseria meningitidis serogroup a CPS and a carba-analogue: Implications for vaccine development.

Carbohydr Res 2019 Dec 16;486:107838. Epub 2019 Oct 16.

Department of Computer Science, University of Cape Town, Rondebosch, 7701, South Africa. Electronic address:

Neisseria meningitidis is a major cause of bacterial meningitis worldwide, especially in Africa. The capsular polysaccharide is the main virulence factor and the target antigen for polysaccharide- and conjugate vaccines. Three tetravalent conjugate vaccines against serogroups A, C, Y and W have been licensed and the monovalent MenAfriVac® was introduced to address the high burden of serogroup A disease in the Meningitis Belt of sub-Saharan Africa. Three of these four vaccines are lyophilized due to the instability of the serogroup A antigen (MenA) in aqueous solution, resulting in a two vial presentation with concomitant additional costs for storage and distribution. Replacement of the saccharide ring oxygen with a methylene group is a promising approach to preparing a stable oligosaccharide MenA analogue (Carba-MenA) vaccine suitable for a liquid formulation. However, to be effective, Carba-MenA must elicit an immune response that is cross-reactive to the native MenA. Here we employ microsecond molecular dynamics simulations of ten repeats of MenA and Carba-MenA to establish that there are significant differences in the conformation and dynamics of these antigens in solution. Carba-MenA has a more random extended, conformation than MenA; MenA has a significant population of compact S-bend conformations that are absent in the analogue. We also find that the disaccharides are poor models of the conformational behaviour of longer chains. This information is relevant for the rational design of optimal analogues for conjugate vaccines.
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http://dx.doi.org/10.1016/j.carres.2019.107838DOI Listing
December 2019

A Mechanistic Study of a Potent and Selective Epidermal Growth Factor Receptor Inhibitor against the L858R/T790M Resistance Mutation.

Biochemistry 2019 10 7;58(41):4246-4259. Epub 2019 Oct 7.

Department of Computer Science , University of Cape Town , Cape Town 7701 , South Africa.

Covalent targeting is a promising strategy for increasing the potency and selectivity of potential drug candidates. This therapeutic approach was recently reported for the epidermal growth factor receptor (EGFR), wherein a covalent binder, [-(3-{7-[2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-3-isopropyl-2,4-dioxopyrimido[4,5-]pyrimidin-1(2)-yl}phenyl)acrylamide], demonstrated significant selectivity and inhibitory activity toward the EGFR L858R/T790M double mutant (EGFR) relative to the EGFR wild-type form (EGFR). The enhanced therapeutic potency of against EGFR is 263 times greater than that against EGFR, which necessitates a rational explanation for the underlying selective and inhibitory mechanisms. In this work, we investigate the differential binding modes of with EGFR and EGFR using molecular dynamics simulations coupled with free energy calculations and further identify key residues involved in the selective targeting, binding, and inhibitory mechanisms mediated by . We find that systematic orientational and conformational changes in the α-loop, p-loop, active loop, and αC-helix are responsible for the disparate binding mechanisms and inhibitory prowess of with respect to EGFR and EGFR. The calculated binding free energies show good correlation with the experimental biological activity. The total binding free energy difference between EGFR- and EGFR- is -11.47 kcal/mol, implying that binds more strongly to EGFR. This enhanced binding affinity of for EGFR is a result of a large increase in the van der Waals and electrostatic interactions with three critical residues (Met790, Gln791, and Met793) that are chiefly responsible for the high-affinity interactions mediated by with EGFR relative to EGFR.
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http://dx.doi.org/10.1021/acs.biochem.9b00710DOI Listing
October 2019

O-acetylation of typhoid capsular polysaccharide confers polysaccharide rigidity and immunodominance by masking additional epitopes.

Vaccine 2019 06 31;37(29):3866-3875. Epub 2019 May 31.

Division of Bacteriology, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK. Electronic address:

In this work, we explore the effects of O-acetylation on the physical and immunological characteristics of the WHO International Standards of Vi polysaccharide (Vi) from both Citrobacter freundii and Salmonella enterica serovar Typhi. We find that, although structurally identical according to NMR, the two Vi standards have differences with respect to susceptibility to de-O-acetylation and viscosity in water. Vi standards from both species have equivalent mass and O-acetylation-dependent binding to a mouse monoclonal antibody and to anti-Vi polyclonal antisera, including the WHO International Standard for human anti-typhoid capsular Vi PS IgG. This study also confirms that human anti-Vi sera binds to completely de-O-acetylated Vi. Molecular dynamics simulations provide conformational rationales for the known effect of de-O-acetylation both on the viscosity and antigenicity of the Vi, demonstrating that de-O-acetylation has a very marked effect on the conformation and dynamic behavior of the Vi, changing the capsular polysaccharide from a rigid helix into a more flexible coil, as well as enhancing the strong interaction of the polysaccharide with sodium ions. Partial de-O-acetylation of Vi revealed hidden epitopes that were recognized by human and sheep anti-Vi PS immune sera. These findings have significance for the manufacture and evaluation of Vi vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2019.05.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997886PMC
June 2019

Conformation and Cross-Protection in Group B Streptococcus Serotype III and Serotype 14: A Molecular Modeling Study.

Pharmaceuticals (Basel) 2019 Feb 13;12(1). Epub 2019 Feb 13.

Department of Chemistry, University of Cape Town, Cape Town 7701, South Africa.

Although the branched capsular polysaccharides of serotype III (GBSIII PS) and serotype 14 (Pn14 PS) differ only in the addition of a terminal sialic acid on the GBSIII PS side chains, these very similar polysaccharides are immunogenically distinct. Our simulations of GBSIII PS, Pn14 PS and the unbranched backbone polysaccharide provide a conformational rationale for the different antigenic epitopes identified for these PS. We find that side chains stabilize the proximal β dGlc(1→6) β dGlcNAc backbone linkage, restricting rotation and creating a well-defined conformational epitope at the branch point. This agrees with the glycotope structure recognized by an anti-GBSIII PS functional monoclonal antibody. We find the same dominant solution conformation for GBSIII and Pn14 PS: aside from the branch point, the backbone is very flexible with a "zig-zag" conformational habit, rather than the helix previously proposed for GBSIII PS. This suggests a common strategy for bacterial evasion of the host immune system: a flexible backbone that is less perceptible to the immune system, combined with conformationally-defined branch points presenting human-mimic epitopes. This work demonstrates how small structural features such as side chains can alter the conformation of a polysaccharide by restricting rotation around backbone linkages.
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http://dx.doi.org/10.3390/ph12010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469160PMC
February 2019

Conformations of Neisseria meningitidis serogroup A and X polysaccharides: The effects of chain length and O-acetylation.

Carbohydr Res 2018 07 22;465:44-51. Epub 2018 Jun 22.

Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. Electronic address:

Neisseria meningitidis is a major cause of bacterial meningitis worldwide especially in Africa. The capsular polysaccharide (CPS) is the main virulence factor and the target antigen for polysaccharide and conjugate vaccines. The high burden of serogroup A disease in the Meningitis Belt of sub-Saharan Africa led to the introduction of MenAfriVac, which has successfully reduced the number of cases of group A disease. However, several outbreaks caused by other serogroups have been reported, including those due to serogroup X. The capsular polysaccharides of serogroups A and X are both homopolymers of amino sugars (α-D-ManNAc and α-D-GlcNAc) containing phosphodiester linkages at C-6 and C-4, respectively. The similarity of the primary structures of the two polysaccharides suggests that serogroup A vaccination may provide cross-protection against serogroup X disease. Molecular dynamics simulations of a series of serogroup A and X oligosaccharides reveal that the MenA CPS behaves as a flexible random coil which becomes less conformationally defined as the length increases, whereas serogroup X forms a more stable regular helical structure. The presence of the MenX helix is supported by NMR analysis; it has four residues per turn and becomes more stable as the chain length increases. Licensed MenA vaccines are largely O-acetylated at C-3: simulations show that these O-acetyl groups are highly solvent exposed and their presence favors more extended conformations compared to the more compact conformations of MenA without O-acetylation. These findings may have implications for the design of optimal conjugate vaccines.
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http://dx.doi.org/10.1016/j.carres.2018.06.007DOI Listing
July 2018

Genetic and structural elucidation of capsular polysaccharides from Streptococcus pneumoniae serotype 23A and 23B, and comparison to serotype 23F.

Carbohydr Res 2017 Oct 18;450:19-29. Epub 2017 Aug 18.

LimmaTech Biologics AG, Grabenstrasse 3, Schlieren, Switzerland.

Streptococcus pneumoniae is a globally important encapsulated human pathogen with approximately 100 different serotypes recognized. Serogroup 23 consists of serotype 23F, present in licensed vaccines, and emerging serotypes 23A and 23B. Here, we report the previously unknown structures of the pneumococcal capsular polysaccharides serotype 23A and 23B determined using genetic analysis, NMR spectroscopy, composition and linkage analysis and Smith degradation (of polysaccharide 23A). The structure of the serotype 23A capsular polysaccharide is: →4)-β-D-Glcp-(1→3)-[[α-L-Rhap-(1→2)]-[Gro-(2→P→3)]-β-D-Galp-(1→4)]-β-L-Rhap-(1→. This structure differs from polysaccharide 23F as it features a disaccharide backbone and the di-substituted β-Gal is linked to β-Rha as a side chain. This is due to the different polymerization position catalysed by the unusually divergent repeat unit polymerase Wzy in the 23A cps biosynthesis locus. Steric crowding in 23A, confirmed by molecular models, causes the NMR signal for H-1 of the di-substituted 2,3-β-Gal to resonate in the α-anomeric region. The structure of the serotype 23B capsular polysaccharide is the same as 23F, but without the terminal α-Rha: →4)-β-D-Glcp-(1→4)-[Gro-(2→P→3)]-β-D-Galp-(1→4)-β-L-Rhap-(1→. The immunodominant terminal α-Rha of 23F is more sterically crowded in 23A and absent in 23B. This may explain the reported typing cross reactions for serotype 23F: slight with 23A and none with 23B.
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http://dx.doi.org/10.1016/j.carres.2017.08.006DOI Listing
October 2017

Cross-protection in Neisseria meningitidis serogroups Y and W polysaccharides: A comparative conformational analysis.

Carbohydr Res 2017 Jun 10;446-447:40-47. Epub 2017 May 10.

Department of Chemistry, University of Cape Town, Cape Town, 7701, South Africa.

The capsular polysaccharide is the main virulence factor in meningococcus. The capsular polysaccharides for meningococcal serogroups Y and W are almost identical polymers of hexose-sialic acid, suggesting the possibility of cross-protection between group Y and W vaccines. However, early studies indicated that they elicit different levels of cross-protection. Here we explore the conformations of the meningococcal Y and W polysaccharides with molecular dynamics simulations of three repeating unit oligosaccharide strands. We find differences in Y and W antigen conformation: the Y polysaccharide has a single dominant conformation, whereas W exhibits a family of conformations including the Y conformation. This result is supported by our NMR NOESY analysis, which indicates key close contacts for W that are not present in Y. These conformational differences provide an explanation for the different levels of cross-protection measured for the Y and W monovalent vaccines and the high group W responses observed in HibMenCY-TT vaccinees.
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http://dx.doi.org/10.1016/j.carres.2017.05.004DOI Listing
June 2017

Fluorescence and NMR spectroscopy together with molecular simulations reveal amphiphilic characteristics of a biofilm exopolysaccharide.

J Biol Chem 2017 06 3;292(26):11034-11042. Epub 2017 May 3.

the Department of Life Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy

Biofilms are a collective mode of bacterial life in which a self-produced matrix confines cells in close proximity to each other. Biofilms confer many advantages, including protection from chemicals (including antibiotics), entrapment of useful extracellular enzymes and nutrients, as well as opportunities for efficient recycling of molecules from dead cells. Biofilm matrices are aqueous gel-like structures composed of polysaccharides, proteins, and DNA stabilized by intermolecular interactions that may include non-polar connections. Recently, polysaccharides extracted from biofilms produced by species of the complex were shown to possess clusters of rhamnose, a 6-deoxy sugar with non-polar characteristics. Molecular dynamics simulations are well suited to characterizing the structure and dynamics of polysaccharides, but only relatively few such studies exist of their interaction with non-polar molecules. Here we report an investigation into the hydrophobic properties of the exopolysaccharide produced by strain C1576. Fluorescence experiments with two hydrophobic fluorescent probes established that this polysaccharide complexes hydrophobic species, and NMR experiments confirmed these interactions. Molecular simulations to model the hydrodynamics of the polysaccharide and the interaction with guest species revealed a very flexible, amphiphilic carbohydrate chain that has frequent dynamic interactions with apolar molecules; both hexane and a long-chain fatty acid belonging to the quorum-sensing system of were tested. A possible role of the non-polar domains of the exopolysaccharide in facilitating the diffusion of aliphatic species toward specific targets within the biofilm aqueous matrix is proposed.
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http://dx.doi.org/10.1074/jbc.M117.785048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491786PMC
June 2017

CarbBuilder: Software for building molecular models of complex oligo- and polysaccharide structures.

J Comput Chem 2016 08 18;37(22):2098-105. Epub 2016 Jun 18.

Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, S-106 91, Sweden.

CarbBuilder is a portable software tool for producing three-dimensional molecular models of carbohydrates from the simple text specification of a primary structure. CarbBuilder can generate a wide variety of carbohydrate structures, ranging from monosaccharides to large, branched polysaccharides. Version 2.0 of the software, described in this article, supports monosaccharides of both mammalian and bacterial origin and a range of substituents for derivatization of individual sugar residues. This improved version has a sophisticated building algorithm to explore the range of possible conformations for a specified carbohydrate molecule. Illustrative examples of models of complex polysaccharides produced by CarbBuilder demonstrate the capabilities of the software. CarbBuilder is freely available under the Artistic License 2.0 from https://people.cs.uct.ac.za/~mkuttel/Downloads.html. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcc.24428DOI Listing
August 2016

Capsular polysaccharide conformations in pneumococcal serotypes 19F and 19A.

Carbohydr Res 2015 Apr 14;406:27-33. Epub 2015 Jan 14.

Department of Chemistry, University of Cape Town, Cape Town, South Africa.

Streptococcus pneumoniae is a significant pathogen in children. Although the PCV7 pneumococcal conjugate vaccine has reduced pneumococcal disease, non-vaccine serotype 19A infection has increased, despite expectations of cross-protection from vaccine serotype 19F. Serotype 19A is included in the new PCV13 vaccine, but not in PCV10. In the solution simulations of 19F and 19A oligosaccharide chains reported here, both polysaccharides form unstructured random coils, with inflexible repeat units linked by mobile phosphodiester linkages. However, there are clear conformational differences. In the 19F repeat unit, the rhamnose residue is nearly orthogonal to the other residues, whereas 19A has residues in similar orientations. This finding is corroborated by key inter-residue distances calculated from NMR NOESY experiments. Further, 19F is predominantly in extended conformations, whereas 19A exhibits a high prevalence of tight hairpin bends. These conformational differences may account for a lack of antibody cross-protection between serotypes 19F and 19A.
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http://dx.doi.org/10.1016/j.carres.2014.12.013DOI Listing
April 2015

Efficient compression of molecular dynamics trajectory files.

J Comput Chem 2012 Oct 25;33(27):2131-41. Epub 2012 Jun 25.

Department of Computer Science, University of Cape Town, Cape Town, South Africa.

We investigate whether specific properties of molecular dynamics trajectory files can be exploited to achieve effective file compression. We explore two classes of lossy, quantized compression scheme: "interframe" predictors, which exploit temporal coherence between successive frames in a simulation, and more complex "intraframe" schemes, which compress each frame independently. Our interframe predictors are fast, memory-efficient and well suited to on-the-fly compression of massive simulation data sets, and significantly outperform the benchmark BZip2 application. Our schemes are configurable: atomic positional accuracy can be sacrificed to achieve greater compression. For high fidelity compression, our linear interframe predictor gives the best results at very little computational cost: at moderate levels of approximation (12-bit quantization, maximum error ≈ 10(-2) Å), we can compress a 1-2 fs trajectory file to 5-8% of its original size. For 200 fs time steps-typically used in fine grained water diffusion experiments-we can compress files to ~25% of their input size, still substantially better than BZip2. While compression performance degrades with high levels of quantization, the simulation error is typically much greater than the associated approximation error in such cases.
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http://dx.doi.org/10.1002/jcc.23050DOI Listing
October 2012

Simulation of Coarse-Grained Protein-Protein Interactions with Graphics Processing Units.

J Chem Theory Comput 2010 Nov;6(11):3588-600

Department of Computer Science,University of Cape Town, Cape Town, South Africa and Department of Chemistry, Cambridge University, Cambridge, United Kingdom.

We report a hybrid parallel central and graphics processing units (CPU-GPU) implementation of a coarse-grained model for replica exchange Monte Carlo (REMC) simulations of protein assemblies. We describe the design, optimization, validation, and benchmarking of our algorithms, particularly the parallelization strategy, which is specific to the requirements of GPU hardware. Performance evaluation of our hybrid implementation shows scaled speedup as compared to a single-core CPU; reference simulations of small 100 residue proteins have a modest speedup of 4, while large simulations with thousands of residues are up to 1400 times faster. Importantly, the combination of coarse-grained models with highly parallel GPU hardware vastly increases the length- and time-scales accessible for protein simulation, making it possible to simulate much larger systems of interacting proteins than have previously been attempted. As a first step toward the simulation of the assembly of an entire viral capsid, we have demonstrated that the chosen coarse-grained model, together with REMC sampling, is capable of identifying the correctly bound structure, for a pair of fragments from the human hepatitis B virus capsid. Our parallel solution can easily be generalized to other interaction functions and other types of macromolecules and has implications for the parallelization of similar N-body problems that require random access lookups.
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http://dx.doi.org/10.1021/ct1003884DOI Listing
November 2010

Visualisation of cyclic and multi-branched molecules with VMD.

J Mol Graph Model 2009 Sep 4;28(2):131-9. Epub 2009 May 4.

Computer Science Department, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.

We report the addition of two visualisation algorithms, termed PaperChain and Twister, to the freely available Visual Molecular Dynamics (VMD) package. These algorithms produce visualisations of complex cyclic molecules and multi-branched polysaccharides and are a generalization and optimization of those we previously developed in a standalone package for carbohydrates. PaperChain highlights each ring in a molecular structure with a polygon, which is coloured according to the ring pucker. Twister traces glycosidic bonds with a ribbon that twists according to the relative orientation of successive sugar residues. Combination of these novel algorithms and new ring selection statements with the large set of visualisations already available in VMD allows for unprecedented flexibility in the level of detail displayed for glycoconjugate, glycoprotein and carbohydrate-binding protein structures, as well as other cyclic structures. We highlight the efficacy of these algorithms with selected illustrative examples, clearly demonstrating the value of the new visualisations, not only for structure validation, but also for facilitating insights into molecular structure and mechanism.
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http://dx.doi.org/10.1016/j.jmgm.2009.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158682PMC
September 2009

Conformational free energy maps for globobiose (alpha-D-Galp-(1-->4)-beta-D-Galp) in implicit and explicit aqueous solution.

Carbohydr Res 2008 May 5;343(6):1091-8. Epub 2008 Feb 5.

Department of Computer Science, University of Cape Town, Cape Town, South Africa.

Four Ramachandran maps of the conformational potential of mean force (PMF) for the galactose disaccharide globobiose (alpha-D-Galp-(1-->4)-beta-D-Galp) were calculated in vacuum, explicit water, with a simple high dielectric constant and a distance-dependent dielectric coefficient, respectively. This simple model of the galactan alpha-(1-->4)-linkage is shown to be conformationally restricted, with only a small range of syn-phi/syn-psi conformations predominating at standard temperature and pressure. This has implications for the preferred conformation and chain dynamics of alpha-galactosides. In addition, comparison of the relevant PMF surfaces reveals the substitution of a high dielectric constant for explicit water solution to be a valid approximation for reproducing the minimum energy conformation of this glycosidic linkage.
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http://dx.doi.org/10.1016/j.carres.2008.01.038DOI Listing
May 2008

Free energy surfaces for the alpha(1 --> 4)-glycosidic linkage: implications for polysaccharide solution structure and dynamics.

J Phys Chem B 2005 Apr;109(15):7468-74

Department of Chemistry, University of Cape Town, Cape Town, South Africa.

We present a potential of mean force surface for rotation about phi and psi dihedral angles of the alpha(1 --> 4)-glycosidic linkage in the maltose disaccharide (4-O-alpha-d-glucopyranosyl-d-glucopyranose) in aqueous solution. Comparison of the vacuum and solution free energy surfaces for maltose shows the principal effects of water to be an increase in the rotational freedom of the alpha(1 --> 4) linkage brought about by lowering the energy barrier for syn to anti conformational changes as well as expansion of the range of low-energy phi,psi conformations. This free energy analysis thus provides a thermodynamic and conformational rationale for the effects of water on alpha(1 --> 4)-linked polysaccharides and carbohydrate glasses.
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http://dx.doi.org/10.1021/jp044756mDOI Listing
April 2005

Ramachandran free-energy surfaces for disaccharides: trehalose, a case study.

Carbohydr Res 2005 Apr;340(5):875-9

Department of Chemistry, University of Cape Town, Cape Town, South Africa.

We present calculated potential of mean force surfaces for rotation about phi, psi dihedral angles of the alpha(1<-->1)alpha-glycosidic linkage in the disaccharide trehalose (alpha-D-Glc-(1<-->1)-alpha-D-Glc) in both vacuum and aqueous solution. The effects of aqueous solvation upon the alpha(1<-->1)alpha-glycosidic linkage are investigated through comparison of the vacuum and aqueous solution free-energy surfaces. These surfaces reveal that trehalose is restricted to a single minimum-energy conformation in both vacuum and solution. The exceptional rigidity of this disaccharide in solution may provide a molecular rationale for the antidesiccant properties of trehalose glasses.
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http://dx.doi.org/10.1016/j.carres.2005.01.031DOI Listing
April 2005