A Combined SAXS and MD Simulation Stud

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE

Article

Multiple Conformational States Contribute to the 3D Structure of a Glucan Decasaccharide: A Combined SAXS and MD Simulation Study Sunhwan Jo, Daniel Myatt, Yifei Qi, James Doutch, Luke Ashley Clifton, Wonpil Im, and Göran Widmalm J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b11085 • Publication Date (Web): 22 Dec 2017 Downloaded from http://pubs.acs.org on December 22, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry B is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Multiple Conformational States Contribute to the 3D Structure of a Glucan Decasaccharide: A Combined SAXS and MD Simulation Study

Sunhwan Jo1, Daniel Myatt2, Yifei Qi3, James Doutch2, Luke A. Clifton2, Wonpil Im4 and Göran Widmalm5,* 1

Leadership Computing Facility, Argonne National Laboratory, 9700 Cass Ave, Argonne, IL

60439, USA 2

ISIS Pulsed Neutron and Muon Source, Science and Technology Facilities Council, Rutherford

Appleton Laboratory, Harwell, Oxfordshire OX11 OQX, UK 3

College of Chemistry and Molecular Engineering, East China Normal University, Shanghai,

200062, China 4

Department of Biological Sciences and Bioengineering, Lehigh University, Bethlehem, PA 18015,

USA 5

Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91

Stockholm, Sweden

ABSTRACT The inherent flexibility of carbohydrates is dependent on stereochemical arrangements, and characterization of their influence and importance will give insight into 3D structure and dynamics. In this study, a β-(1→4)/β-(1→3)-linked glucosyl decasaccharide is experimentally investigated by synchrotron small-angle X-ray scattering from which its radius of gyration (Rg) is obtained. Molecular dynamics (MD) simulations of the decasaccharide show four populated states at each glycosidic linkage, namely, syn- and anti-conformations. The calculated Rg values from the MD simulation reveal that in addition to syn-conformers, the presence of anti-ψ conformational states are required to reproduce experimental scattering data, unveiling inherent glycosidic linkage flexibility. The CHARMM36 force field for carbohydrates thus describes the conformational flexibility of the decasaccharide very well and captures the conceptual importance that anticonformers are to be anticipated at glycosidic linkages of carbohydrates.

1 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

INTRODUCTION Carbohydrates are found as structural components in the plant kingdom in the form of cellulose and hemicellulose;1 whereas the former is made of β-(1→4)-linked glucosyl residues and the latter can include several different monosaccharides.2 In contrast, as a source of stored energy, the glucosyl residues are α-linked in its two constituent polysaccharides amylose and amylopectin. The glycans in mammals and invertebrates form highly complex glycoconjugates from a limited number of different sugar residues, whereas in bacteria the number of various sugars is two orders of magnitude larger, facilitating an immense structural variety.3 The combinatorial nature of these structures thus poses an intricate problem and, if the three-dimensional (3D) structure is added to the permutation aspects of glycans, the challenges become even more formidable. The properties of carbohydrates are governed by their primary structure, shape, charge, flexibility and dynamics, which can be determined by various biophysical methods. For glycans in solution, NMR spectroscopy is of utmost importance,4 but other techniques such as size exclusion chromatography with multi angle laser light scattering and viscometry (SEC-MALLS-VISC),5 circular dichroism (CD) spectroscopy,6 Raman optical activity (ROA) and infrared (IR) spectroscopy7 contribute to the characterization of their structures and properties. Small-angle scattering (SAS) utilizing X-rays (SAXS) or neutrons (SANS)8 in combination with techniques such as analytical ultracentrifugation,9 dynamic light scattering, or size exclusion chromatography10 have been used to elucidate size and shape of proteins; application of all-atom modeling in combination with SAXS data of glycoproteins facilitates generation of models that are in excellent agreement to scattering data and consequently the spatial distribution of glycan chains can be deduced for this class of glycoconjugates.11 The major degrees of freedom of an oligo- or polysaccharide giving rise to their flexibility and dynamics over time are the torsion angles φ and ψ at the glycosidic linkage.12 The flexibility of the ω torsion angle for hydroxymethyl groups in hexopyranoses such as glucose or similar exocyclic torsions in higher-carbon sugars such as sialic acid with (2→8)- and (2→9)-linkages is also of importance,13 together with inherent ring-flexibility in the monosaccharide per se, e.g., α-L-iduronic acids present in heparin or xylose and its derivatives.14,15 The φ torsion angle mainly populates the exo-anomeric conformation, but non-exo-anomeric conformations may be present to some extent. The ψ torsion angle is populating conformational states close to ψH ≈ 0°, where ψH is defined by C1'-Ox-Cx-Hx and x refers to the linkage position, leading to syn-conformations, but anti-ψ conformations (ψH ≈ 180°) can also be populated. For the ω torsion angle O5-C5-C6-O6, two conformational states referred to as gauche-trans and gauche-gauche with respect to O5 and C4, 2 ACS Paragon Plus Environment

Page 2 of 17

Page 3 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


respectively, are significantly populated, the specific one favored being dependent on the monosaccharide, i.e., whether it has the gluco- or galacto-configuration.16 To a large extent, NMR spectroscopy has been utilized to obtain this kind of conformational information in conjunction with molecular modeling and molecular dynamics (MD) simulations. The extent to which anti-conformers17,18 are present in solution has been discussed based on the NMR spectroscopy measurements.19,20 We have previously studied the decasaccharide β-D-Glcp(1→4)-β-D-Glcp-(1→3)-β-D-Glcp-(1→4)-β-D-Glcp-(1→3)-β-D-Glcp-(1→4)-β-D-Glcp-(1→3)-β-DGlcp-(1→4)-β-D-Glcp-(1→3)-β-D-Glcp-(1→4)-β-D-Glcp-OMe (1) (Figure 1) by NMR residual dipolar couplings and 1D 1H,1H-NOESY experiments in conjunction with molecular modeling21 with focus on the conformational preference(s) of the central β-(1→4)-linkage using a highly deuterated isotopologue of the decasaccharide.22 It was shown that the major conformational state at this linkage can be described by a syn-conformation with the φ torsion in the exo-anomeric conformation. In this study, we obtain information on glycosidic linkage flexibility by acquiring SAXS data of 1 and analyze and interpret the experimental results aided by MD simulations.

Figure 1. Schematic of decasaccharide 1 with glycosidic torsion angles annotated. [Publisher: use two-column-width]

MATERIALS AND METHODS General Considerations. The synthesis of the decasaccharide β-D-Glcp-(1→4)-β-D-Glcp-(1→3)β-D-Glcp-(1→4)-β-D-Glcp-(1→3)-β-D-Glcp-(1→4)-β-D-Glcp-(1→3)-β-D-Glcp-(1→4)-β-D-Glcp(1→3)-β-D-Glcp-(1→4)-β-D-Glcp-OMe was reported previously.22 For the SAXS experiments the d67-deuterated isotopologue was used. The glycosidic torsion angles are defined as follows: φ = H1(n)-C1(n)-Ox(n+1)-Cx(n+1) and ψ = C1(n)-Ox(n+1)-Cx(n+1)-Hx(n+1), where x is the linkage position and n denotes the glucosyl residue in the decasaccharide, numbered from the terminal nonreducing end. Small-angle x-ray scattering experiments. SAXS data sets from the saccharide sample were obtained at the B21 beamline at the Diamond Light Source (Harwell, UK).23,24,25 The decasaccharide sample and buffer solution were exposed to the beam in a 1.6 mm diameter quartz capillary which was loaded using an Arinax (Grenoble, France) BioSAXS automated sample changer robot. The exposure unit temperature was set to 15 °C. The sample capillary was held in 3 ACS Paragon Plus Environment


vacuum and cleaned between each measurement. Samples were stored in 96 well plates at 5 °C. SAXS data was collected on a Pilatus 2M two-dimensional detector. A total of 180 frame exposures of 1 s from the sample and the corresponding buffer were summed to produce each data set. Each frame was examined for the presence of radiation-induced sample damage; where this was found the frames were not reduced and further processed. The detector was 3.9 m from the sample position, yielding a Q-range of 0.012 Å−1 < 0.4 Å−1. Q = 4π sin θ / λ, where 2θ is the scattering angle and λ is the wavelength, which is this case was 1 Å. Two-dimensional data reduction consisted of normalization for beam current and sample transmission, radial sector integration, background buffer subtraction and averaging. Further data analysis, such as scaling, merging and Guinier analysis were performed in PRIMUS.26 Molecular dynamics simulations. We have used the Glycan Fragment Database (GFDB; http://www.glycanstructure.org/fragment-db)27 to model the glycan conformation for the MD simulation. Employing the GFDB, PDB entries that contain the sequences of β-D-Glcp-(1→3)-β-DGlcp and β-D-Glcp-(1→4)-β-D-Glcp and whose resolution is less than 3 Å were searched. The filtering options provided by the GFDB were used to remove distorted residues and redundant entries. The major glycosidic linkage torsion angle populations were selected and the initial model was generated using the IC EDIT facility in CHARMM simulation software.28 Glycan Reader29 and Quick MD Simulator in CHARMM-GUI30 were used to build a solvated MD simulation system. The system size was determined so that the resulting systems have at least a water layer of 12.5 Å in x, y, and z directions. The solvated simulation systems were minimized while the positional harmonic restraints were applied to the non-hydrogen atoms of the decasaccharide using CHARMM simulation software28 followed by a 4-ns equilibration simulation at 288 K using the NPT (constant particle number, pressure and temperature) ensemble and NAMD simulation software.31,32 All simulations were performed using the recently updated CHARMM36 carbohydrate force field33,34 and TIP3P water model.35 The van der Waals interactions were smoothly switched off between 10 and 12 Å by a forced-based switching function.36 Long-range electrostatic interactions were calculated using the particle-mesh Ewald (PME) method.37 An interpolation order of 6 and a direct space tolerance of 10-6 were used for the PME method. A time-step of 2 fs was used with the SHAKE algorithm.38 For the NAMD simulations, Langevin dynamics was used to maintain constant temperatures for each system, while the Nose-Hoover Langevin-piston algorithm39,40 was used to maintain constant pressure at 1 bar. The equilibrated simulation system was used as an initial configuration for a replica-exchange simulation (REMD). A variant of REMD, namely replica-exchange solute tempering (REST2),41,42 was used to accelerate the sampling of glycosidic linkage conformations. In REST2 algorithm, the 4 ACS Paragon Plus Environment

Page 4 of 17

Page 5 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


simulation system is decomposed into solute and solvent components, and the solute-solute and solute-solvent interaction energy are scaled, which mimics the effect of increasing temperature of the solute. A recently implemented REST2 module for NAMD simulation package was used.43 A total of 16 replicas were used to cover the effective temperature range from 288 K to 650 K and the simulations were performed for 60 ns at 1.01325 bar using the NPT ensemble. Coarse-graining of conformational states using glycosidic torsion angles. The torsion angle distribution from the target temperature replica (288 K) in the REST2 simulation was used to identify a set of conformational basins as described by Jo et al.44 The decasaccharide conformation can be described with a 9-letter notation (states A – D), starting from residue 1 (terminal end) in Figure 1. For example, ‘AAAAAAAAA’ indicates that all glycosidic (߶, ߰) torsion angles adopt a conformation corresponding to the largest basin. SAXS profile from simulation trajectory. The representative structures for each coarse-grained conformational state were generated by assigning the corresponding central glycosidic (߶, ߰) torsion angles using IC EDIT facility in CHARMM software package.28 The SAXS profile was then computed for each representative structure using CRYSOL program45 with the explicit hydrogen and constant subtraction options. The experimental SAXS curve was then fitted against the theoretical computation. In addition, REMD simulation trajectory snapshot from the simulation was saved for every 10 ps and subjected to CRYSOL program to compute SAXS profile, after deleting all other molecules except the decasaccharide molecule.

RESULTS AND DISCUSSION The canonical conformation of the D-glucose-containing decasaccharide 1 (Figure 1) is a highly extended rod-like structure, due to the exo (φ) and syn (ψ) conformation46 at the glycosidic linkages. The alternating (1→4)- and (1→3)-linkages of the ten sugar residues result in highly degenerate NMR chemical shifts beyond the disaccharide level and, to study the conformational preference of the central β-(1→4)-linkage, a highly deuterated analogue was used.22 1H,1H-NOESY and 1H,13CRDC NMR experiments revealed that the exo-syn conformation with φ ≈ 30° and ψ ≈ 10° prevailed at this linkage,21 which is referred to as linkage number 5 in this study. However, the negative sign of the trans-glycosidic dipolar coupling between H1 in residue 5 and H4 in residue 6 confirmed that this interaction was close to parallel to the principal axis of the decasaccharide, although it did not disclose any detailed information about the overall shape of the molecule. To obtain further information on conformational preferences, we therefore employed an experimental technique that is rarely used in the study of oligosaccharide structure, viz., SAXS, 5 ACS Paragon Plus Environment


although it was used to study an amylose fragment (maltoheptaose)47 and the solution structure of heparin oligosaccharide conformation in conjunction with ultracentrifugation and constrained molecular modeling.48 Acquiring SAXS data on the decasaccharide as a function of scattering angle facilitates the scattering intensity I(Q) to be analyzed as a function of the scattering vector Q, as shown in Figure 2.

Figure 2. Experimental SAXS data and a fit using the ‘AAAAAACAA’ conformation of 1 resulting in an RG = 13.1 Å.

The interpretation of the experimental SAXS results calls for a molecular description and to this end we carried out an REMD simulation of decasaccharide 1 with explicit water as solvent. Similar conformational states can be identified for both the (1→4)- and (1→3)-linkages (Figure 3), viz, the exo-syn conformation (A), non-exo (B), anti-ψ (C) and anti-φ (D) regions. The conformational state A is the major one for both types of glycosidic linkages, but is more prominent for the β-(1→3)linkage than for the β-(1→4)-linkage (Table 1). Conformational region B is also populated to a significant extent, although for this conformational state it is the β-(1→4)-linkage which is present to a larger degree compared to the β-(1→3)-linkage. The anti-ψ state C is populated to a larger extent than the anti-φ state D for both of the glyosidic linkages. Thus, for the conformational regions the populations are present as A > B > C > D (Table 1).


Page 6 of 17

Page 7 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. Probability density plots of the β-(1→4)-linkages (a) and the β-(1→3)-linkages (b) from the MD simulation of decasaccharide 1 where blue color indicates high probability and white color corresponds to low probability. Conformational states are labeled A – D.

Table 1. Conformational state populations (%) of decasaccharide 1. State

P (χ2 < 0.007)

Pall β-(1→4)

β-(1→3)

Combined

β-(1→4)

β-(1→3)

Combined

A

69.6

86.9

77.3

69.9

90.7

79.1

B

26.0

11.6

19.6

23.6

7.1

16.3

C

4.1

1.3

2.9

6.4

2.0

4.5

D

0.2

0.1

0.2

0.1

0.2

0.1



Page 8 of 17

The glycosidic torsion angles and their fluctuations are compiled in Table 2 and information on each glycosidic linkage is given in Tables S1 and S2. In general, the fluctuations are slightly larger for the ψ torsions than for the φ torsions and the largest fluctuations are observed in region C for the anti-ψ states; the latter is contrasted by the fluctuations in the anti-φ state D for which the torsional flexibility of ψ < φ. At this point we compare the MD simulations to the experimentally derived distance H1[5],H4[6], which is 2.2 ± 0.1 Å21 consistent with high population of conformational states A and B, being 2.28 Å and 2.19 Å, respectively (Table 2).

Table 2. Conformational state dependent glycosidic torsion angles (°) and effective inter-proton distance (Å) of decasaccharide 1; the standard deviation in each state is given in parenthesis. State

β-(1→4)

φ

β-(1→3)

ψ

φ

reff

ψ

H1[5],H4[6]

A

50.6 (10.4)

−2.2 (11.6)

51.6 (12.2)

9.8 (14.2) 2.280 (0.003)

B

32.1 (12.2)

−34.6 (13.1)

32.4 (12.8)

−27.8 (14.5) 2.193 (0.006)

C

56.4 (14.5) −163.5 (16.8)

D

167.8 (11.5)

2.8 (7.9)

48.4 (15.7) −178.4 (19.8) 3.583 (0.005) 169.4 (13.7)

9.6 (11.4) 3.575 (0.017)

How well does the conformational distribution of states from the MD simulation (Table 1) agree with that obtained from experimental SAXS data? The small-angle scattering profiles were theoretically calculated for each frame of the MD simulation, together with the radius of gyration (Rg) of the decasaccharide structures. From the MD simulation, the conformational states A – D at each of the nine glycosidic linkages between sugar residues were monitored, binned and ranked according to population (Table S3 covering > 95%). The highest populated state was ‘all-A’ present to 9.3%. A range of states containing a mixture of A and B in the interval 3.6% – 1.2% was then present before a conformational state having an anti-ψ torsion was observed, viz., ‘AAAAAAACAA’ to 1.1%. Analyzing the goodness of fit χ2 vs. radius of gyration Rg for conformations of the decasaccharide from the MD simulation show Rg ≈ 13 Å for populations (P) having χ2 < 0.007 (Figure 4). Notably, at this level of fit essentially all conformations have at least one of their glycosidic linkages in an anti-ψ state and the C state is increased compared to the MD simulation per se (Table 1). The top five conformations of the decasaccharide from the MD 8 ACS Paragon Plus Environment

Page 9 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


simulation having a C state as part of the sequence and P (χ2 < 0.007) are shown in Figure 5 (cf. also Table S3). Thus, employing SAXS data in the analysis of oligosaccharide conformation shows that anti-ψ conformational states are present and as such the flexibility aspects should be considered when addressing the three-dimensional structure of carbohydrates.

Figure 4. Goodness of fit χ2 vs. radius of gyration Rg (Å) for conformations of 1 from the MD simulation where blue color indicates high probability and white color corresponds to low probability.



Figure 5. Five molecular models of decasaccharide 1 consistent with χ2 < 0.007 for which Rg is spanning 13.0 – 13.1 Å, namely, ‘AAAAAACAA’, ‘AAAACAAAA’, ‘AABAAACAA’, ‘AAAAAAAAC’ and ’AAAACABAA’, from top to bottom.

Mixed-linkage (1→3),(1→4)-β-D-glucans (MLG) are present as cell wall polysaccharides in cereals,49 grasses,50 ferns51 and lichens (mosses)52 where the ratio (1→4)/(1→3)-linked residues is > 1, typically on the order of 2 – 4, but in some cases significantly higher. The polysaccharide structure is consequently a mixture between cellulose and curdlan with shard physical and physiological properties.53 Interestingly, the bacterium Sinorhizobium meliloti produces under regulation of the secondary messenger cyclic diguanolate an MLG that markedly enhances attachment to the host plant root as well as formation of dense biofilms on the surface of roots.54 The MLG produced consists of a disaccharide repeating unit with alternating linkages, viz., →4)-βD-Glcp-(1→3)-β-D-Glcp-(1→,

i.e., the same repeat as in the decasaccharide studied herein. The

conformational preferences deduced for decasaccharide 1 thus have implications on polysaccharide structures from the plant kingdom and when they are produced by bacteria. 10 ACS Paragon Plus Environment

Page 10 of 17

Page 11 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CONCLUSIONS The conformational analysis of oligosaccharides in solution to a large extent relies on acquiring experimental NMR data that subsequently may be interpreted using molecular modeling techniques. The information that can be gained across the glycosidic linkage to assess the conformational aspects is in many cases short-ranged, which leads to difficulties when addressing larger oligosaccharides; the use of NMR residual dipolar couplings is an exception. MD simulations are powerful in obtaining models in which dynamics is also considered in the analysis, yielding information on the presence of anti-conformational states.55 It is encouraging that the CHARMM36 force field for carbohydrates utilized herein describes results from 1H,1H-NOE data very well and that the populations of the structures sampled in the MD simulation per se are close to those obtained when SAXS data was used in obtaining information on the overall structure of the decasaccharide. Most importantly, in order to account for the SAXS data well, the presence of antiψ conformational states is essential, confirming by an ‘orthogonal’ biophysical technique to what has been used previously the importance of these states and that oligosaccharides, as well as polysaccharides,56,57 should be described as dynamic molecules with inherent high flexibility.

Supporting Information Available Tables of glycosidic torsion angles’ averages and of populated states.

AUTHOR INFORMATION Corresponding author. *E-mail: [email protected]

ACKNOWLEDGEMENTS This work was supported by grants from the Swedish Research Council 2013-4859 (G.W.), NSF DBI-1707207, XSEDE MCB070009 (W.I.) and used resources of the Argonne Leadership Computing Facility, which is a DOE Office of Science User Facility supported under Contract DEAC02-06CH11357.

REFERENCES (1)

Chen, H. Chemical Composition and Structure of Natural Lignocellulose. In Biotechnology 11 ACS Paragon Plus Environment


of Lignocellulose: Theory and Practice; Springer Science+Business Media: Dordrecht, 2014; pp 25–71. (2)

Berglund, J.; Angles d’Ortoli, T.; Vilaplana, F.; Widmalm, G.; Bergenstråhle-Wohlert, M.; Lawoko, M.; Henriksson, G.; Lindström, M.; Wohlert, J. A Molecular Dynamics Study of the Effect of Glycosidic Linkage Type in the Hemicellulose Backbone on the Molecular Chain Flexibility. Plant J. 2016, 88, 56–70.

(3)

Adibekian, A.; Stallforth, P.; Hecht, M.-L.; Werz, D. B.; Gagneux, P.; Seeberger, P. H. Comparative Bioinformatics Analysis of the Mammalian and Bacterial Glycomes. Chem. Sci. 2011, 2, 337–344.

(4)

NMR in Glycoscience and Glycotechnology; Kato, K., Peters, T., Eds.; Royal Society of Chemistry: Cambridge, 2017.

(5)

Dalheim, M.; Arnfinnsdottir, N. B.; Widmalm, G.; Christensen, B. E. The Size and Shape of Three Water-Soluble, Non-Ionic Polysaccharides Produced by Lactic Acid Bacteria: A Comparative Study. Carbohydr. Polym. 2016, 142, 91–97.

(6)

Andersson, M.; Kenne, L.; Stenutz, R.; Widmalm, G. Synthesis Of, and NMR and CD Studies On, Methyl 4-O-[(R)- and (S)-1-Carboxyethyl]-α-L-Rhamnopyranoside and Methyl 6-O-[(R)- and (S)-1-Carboxyethyl]-α-D-Galactopyranoside. Carbohydr. Res. 1994, 254, 35– 41.

(7)

Wiercigroch, E.; Szafraniec, E.; Czamara, K.; Pacia, M. Z.; Majzner, K.; Kochan, K.; Kaczor, A.; Baranska, M.; Malek, K. Raman and Infrared Spectroscopy of Carbohydrates: A Review. Spectrochim. Acta - Part A Mol. Biomol. Spectrosc. 2017, 185, 317–335.

(8)

Trewhella, J. Small-Angle Scattering and 3D Structure Interpretation. Curr. Opin. Struct. Biol. 2016, 40, 1–7.

(9)

Perkins, S. J.; Nan, R.; Li, K.; Khan, S.; Abe, Y. Analytical Ultracentrifugation Combined with X-Ray and Neutron Scattering: Experiment and Modelling. Methods 2011, 54, 181–199.

(10)

Clifton, L. A.; Sanders, M. R.; Castelletto, V.; Rogers, S. E.; Heenan, R. K.; Neylon, C.; Frazier, R. A.; Green, R. J. Puroindoline-A, a Lipid Binding Protein from Common Wheat, Spontaneously Forms Prolate Protein Micelles in Solution. Phys. Chem. Chem. Phys. 2011, 13, 8881–8888.

(11)

Guttman, M.; Weinkam, P.; Sali, A.; Lee, K. K. All-Atom Ensemble Modeling to Analyze Small-Angle X-Ray Scattering of Glycosylated Proteins. Structure 2013, 21, 321–331.

(12)

Widmalm, G. A Perspective on the Primary and Three-Dimensional Structures of 12 ACS Paragon Plus Environment

Page 12 of 17

Page 13 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Carbohydrates. Carbohydr. Res. 2013, 378, 123–132. (13)

Yongye, A. B.; Gonzalez-Outeiriño, J.; Glushka, J.; Schultheis, V.; Woods, R. J. The Conformational Properties of Methyl α-(2,8)-Di/trisialosides and Their N-Acyl Analogues: Implications for Anti-Neisseria Meningitidis B Vaccine Design. Biochemistry 2008, 47, 12493–12514.

(14)

Ochsenbein, P.; Bonin, M.; Schenk-Joß, K.; El-Hajji, M. The 2SO Skew-Boat Conformation in L-Iduronic Acid. Angew. Chemie - Int. Ed. 2011, 50, 11637–11639.

(15)

Thorsheim, K.; Siegbahn, A.; Johnsson, R. E.; Stålbrand, H.; Manner, S.; Widmalm, G.; Ellervik, U. Chemistry of Xylopyranosides. Carbohydr. Res. 2015, 418, 65–88.

(16)

Soltesova, M.; Kowalewski, J.; Widmalm, G. Dynamics of Exocyclic Groups in the Escherichia Coli O91 O-Antigen Polysaccharide in Solution Studied by Carbon-13 NMR Relaxation. J. Biomol. NMR 2013, 57, 37–45.

(17)

Dabrowski, J.; Grosskurth, H.; Kožár, T.; Nifant’ev, N. E. Conformational Mobility of Oligosaccharides: Experimental Evidence for the Existence of an “Anti” Conformer of the Galβl-3Glcβ1-OMe Disaccharide. J. Am. Chem. Soc. 1995, 117, 5534–5539.

(18)

Landersjö, C.; Stenutz, R.; Widmalm, G. Conformational Flexibility of Carbohydrates: A Folded Conformer at the Phi Dihedral Angle of a Glycosidic Linkage. J. Am. Chem. Soc. 1997, 119, 8695–8698.

(19)

Larsson, E. A.; Staaf, M.; Soderman, P.; Höög, C.; Widmalm, G. Determination of the Conformational Flexibility of Methyl α-Cellobioside in Solution by NMR Spectroscopy and Molecular Simulations. J. Phys. Chem. A 2004, 108, 3932–3937.

(20)

Martín-Pastor, M.; Canales, A.; Corzana, F.; Asensio, J. L.; Jiménez-Barbero, J. Limited Flexibility of Lactose Detected from Residual Dipolar Couplings Using Molecular Dynamics Simulations and Steric Alignment Methods. J. Am. Chem. Soc. 2005, 127, 3589–3595.

(21)

Lycknert, K.; Maliniak, A.; Widmalm, G. Analysis of Oligosaccharide Conformation by NMR Spectroscopy Utilizing 1H,1H and 1H,13C Residual Dipolar Couplings in a Dilute Liquid Crystalline Phase. J. Phys. Chem. A 2001, 105, 5119–5122.

(22)

Hällgren, C.; Widmalm, G. Synthesis of a Site-Specific Deuterium Substituted Methyl β-DGlucan Decasaccharide. J. Carbohydr. Chem. 1993, 12, 309–333.

(23)

Inoue, K.; Doutch, J.; Terrill, N. The Current Status of Small-Angle X-Ray Scattering Beamline at Diamond Light Source. Bunseki Kagaku 2013, 62, 565–570. 13 ACS Paragon Plus Environment


(24)

Hamley, I. W.; Dehsorkhi, A.; Castelletto, V.; Walter, M. N. M.; Connon, C. J.; Reza, M.; Ruokolainen, J. Self-Assembly and Collagen-Stimulating Activity of a Peptide Amphiphile Incorporating a Peptide Sequence from Lumican. Langmuir 2015, 31, 4490–4495.

(25)

Sharma, U.; Carrique, L.; Vadon-Le Goff, S.; Mariano, N.; Georges, R. N.; Delolme, F.; Koivunen, P.; Myllyharju, J.; Moali, C.; Aghajari, N.; et al. Structural Basis of Homo- and Heterotrimerization of Collagen I. Nat. Commun. 2017, 8, 14671.

(26)

Konarev, P. V.; Volkov, V. V.; Sokolova, A. V.; Koch, M. H. J.; Svergun, D. I. PRIMUS: A Windows PC-Based System for Small-Angle Scattering Data Analysis. J. Appl. Crystallogr. 2003, 36, 1277–1282.

(27)

Jo, S.; Im, W. Glycan Fragment Database: A Database of PDB-Based Glycan 3D Structures. Nucleic Acids Res. 2013, 41, D470–D474.

(28)

Brooks, B. R.; Brooks III, C. L.; Mackerell Jr., A. D.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; et al. CHARMM. J. Comput. Chem. 2009, 30, 1545–1614.

(29)

Jo, S.; Song, K. C.; Desaire, H.; MacKerell Jr, A. D.; Im, W. Glycan Reader: Automated Sugar Identification and Simulation Preparation for Carbohydrates and Glycoproteins. J. Comput. Chem. 2011, 32, 3135–3141.

(30)

Jo, S.; Kim, T.; Iyer, V. G.; Im, W. CHARMM-GUI: A Web-Based Graphical User Interface for CHARMM. J. Comput. Chem. 2008, 29, 1859–1865.

(31)

Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kalé, L.; Schulten, K. Scalable Molecular Dynamics with NAMD. J. Comput. Chem. 2005, 26, 1781–1802.

(32)

Lee, J.; Cheng, X.; Swails, J. M.; Yeom, M. S.; Eastman, P. K.; Lemkul, J. A.; Wei, S.; Buckner, J.; Jeong, J. C.; Qi, Y.; et al. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J. Chem. Theory Comput. 2016, 12, 405–413.

(33)

Guvench, O.; Hatcher, E. R.; Venable, R. M.; Pastor, R. W.; Mackerell Jr, A. D. CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses. J. Chem. Theory Comput. 2009, 5, 2353–2370.

(34)

Patel, D. S.; Pendrill, R.; Mallajosyula, S. S.; Widmalm, G.; Mackerell Jr, A. D. Conformational Properties of α- or β-(1→6)-Linked Oligosaccharides: Hamiltonian Replica Exchange MD Simulations and NMR Experiments. J. Phys. Chem. B 2014, 118, 2815–2871. 14 ACS Paragon Plus Environment

Page 14 of 17

Page 15 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(35)

Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926– 935.

(36)

Steinbach, P. J.; Brooks, B. R. New Spherical-Cutoff Methods for Long-Range Forces in Macromolecular Simulation. J. Comput. Chem. 1994, 15, 667–683.

(37)

Darden, T.; York, D.; Pedersen, L. Particle Mesh Ewald: An N log(N) Method for Ewald Sums in Large Systems. J. Chem. Phys. 1993, 98, 10089–10092.

(38)

Ryckaert, J. P.; Ciccotti, G.; Berendsen, H. J. C. Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of N-Alkanes. J. Comput. Phys. 1977, 23, 327–341.

(39)

Feller, S. E.; Zhang, Y.; Pastor, R. W.; Brooks, B. R. Constant Pressure Molecular Dynamics Simulation: The Langevin Piston Method. J. Chem. Phys. 1995, 103, 4613–4621.

(40)

Martyna, G. J.; Tobias, D. J.; Klein, M. L. Constant Pressure Molecular Dynamics Algorithms. J. Chem. Phys. 1994, 101, 4177–4189.

(41)

Huang, X.; Hagen, M.; Kim, B.; Friesner, R. A.; Zhou, R.; Berne, B. J. Replica Exchange with Solute Tempering: Efficiency in Large Scale Systems. J. Phys. Chem. B 2007, 111, 5405–5410.

(42)

Wang, L.; Friesner, R. A.; Berne, B. J. Replica Exchange with Solute Scaling: A More Efficient Version of Replica Exchange with Solute Tempering (REST2). J. Phys. Chem. B 2011, 115, 9431–9438.

(43)

Jo, S.; Jiang, W. A Generic Implementation of Replica Exchange with Solute Tempering (REST2) Algorithm in NAMD for Complex Biophysical Simulations. Comput. Phys. Commun. 2015, 197, 304–311.

(44)

Jo, S.; Qi, Y.; Im, W. Preferred Conformations of N-Glycan Core Pentasaccharide in Solution and in Glycoproteins. Glycobiology 2015, 26, 19–29.

(45)

Svergun, D.; Barberato, C.; Koch, M. H. CRYSOL - A Program to Evaluate X-Ray Solution Scattering of Biological Macromolecules from Atomic Coordinates. J. Appl. Crystallogr. 1995, 28, 768–773.

(46)

Yang, M.; Angles d’Ortoli, T.; Säwén, E.; Jana, M.; Widmalm, G.; MacKerell Jr, A. D. Delineating the Conformational Flexibility of Trisaccharides from NMR Spectroscopy Experiments and Computer Simulations. Phys. Chem. Chem. Phys. 2016, 18, 18776–18794. 15 ACS Paragon Plus Environment


(47)

Shimada, J.; Kaneko, H.; Takada, T.; Kitamura, S.; Kajiwara, K. Conformation of Amylose in Aqueous Solution: Small-Angle X-Ray Scattering Measurements and Simulations. J. Phys. Chem. B 2000, 104, 2136–2147.

(48)

Khan, S.; Gor, J.; Mulloy, B.; Perkins, S. J. Semi-Rigid Solution Structures of Heparin by Constrained X-Ray Scattering Modelling: New Insight into Heparin-Protein Complexes. J. Mol. Biol. 2010, 395, 504–521.

(49)

Carpita, N. C. Structure and Biogenesis of the Cell Walls of Grasses. Annu. Rev. Plant Physiol. Plant Mol. Biol. 1996, 47, 445–476.

(50)

Vogel, J. Unique Aspects of the Grass Cell Wall. Curr. Opin. Plant Biol. 2008, 11, 301–307.

(51)

Xue, X.; Fry, S. C. Evolution of Mixed-Linkage (1→3, 1→4)-β-D-Glucan (MLG) and Xyloglucan in Equisetum (Horsetails) and Other Monilophytes. Ann. Bot. 2012, 109, 873– 886.

(52)

Simmons, T. J.; Uhrín, D.; Gregson, T.; Murray, L.; Sadler, I. H.; Fry, S. C. An Unexpectedly Lichenase-Stable Hexasaccharide from Cereal, Horsetail and Lichen MixedLinkage β-Glucans (MLGs): Implications for MLG Subunit Distribution. Phytochemistry 2013, 95, 322–332.

(53)

Lazaridou, A.; Biliaderis, C. G.; Micha-Screttas, M.; Steele, B. R. A Comparative Study on Structure-Function Relations of Mixed-Linkage (1→3), (1→4) Linear β-D-Glucans. Food Hydrocoll. 2004, 18, 837–855.

(54)

Pérez-Mendoza, D.; Ángel Rodríguez-Carvajal, M.; Romero-Jiménez, L.; de Araujo Farias, G.; Lloret, J.; Trinidad Gallegos, M.; Sanjuán, J. Novel Mixed-Linkage β-Glucan Activated by c-Di-GMP in Sinorhizobium Meliloti. Proc. Natl. Acad. Sci. 2015, 112, E757–E765.

(55)

Höög, C.; Landersjö, C.; Widmalm, G. Oligosaccharides Display Both Rigidity and High Flexibility in Water as Determined by 13C NMR Relaxation and 1H,1H NOE Spectroscopy: Evidence of Anti-Phi and Anti-Psi Torsions in the Same Glycosidic Linkage. Chem. - A Eur. J. 2001, 7, 3069–3077.

(56)

Tsai, C. C.; Morrow, B. H.; Chen, W.; Payne, G. F.; Shen, J. Toward Understanding the Environmental Control of Hydrogel Film Properties: How Salt Modulates the Flexibility of Chitosan Chains. Macromolecules 2017, 50, 5946–5952.

(57)

Blasco, P.; Patel, D. S.; Engström, O.; Im, W.; Widmalm, G. Conformational Dynamics of the Lipopolysaccharide from Escherichia Coli O91 Revealed by Nuclear Magnetic Resonance Spectroscopy and Molecular Simulations. Biochemistry 2017, 56, 3826–3839. 16 ACS Paragon Plus Environment

Page 16 of 17

Page 17 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC Graphic


A Combined SAXS and MD Simulation Stud

Recommend Documents