Conformational Properties of α- or β-(1→6)-Linked Oligosaccharides: Hamiltonian Replica Exchange MD Simulations and NMR Experiments

Patel, Dhilon S.; Pendrill, Robert; Mallajosyula, Sairam S.; Widmalm, Göran; MacKerell, Alexander D.

doi:10.1021/jp412051v

Cited by 54 publications

(105 citation statements)

References 146 publications

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“…Subsequently, the model has been applied to study glycopeptides, including the anti-proliferative factor, 73 and validated against NMR data for di- and trisaccharides; 74 these efforts included targeting the 1–6 linkage, which led to additional optimization of associated dihedral parameters. 75 The presence of a broad carbohydrate model that is consistent with the remainder of the CHARMM36 force field is anticipated to facilitate studies of complex systems, such as glycolipids, glycoproteins and a range of carbohydrate-containing antibiotics. 76 …”

Section: The Charmm36 Additive Force Fieldmentioning

confidence: 99%

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

Vanommeslaeghe

MacKerell

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

265

235

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Background Molecular Mechanics (MM) is the method of choice for computational studies of biomolecular systems owing to its modest computational cost, which makes it possible to routinely perform molecular dynamics (MD) simulations on chemical systems of biophysical and biomedical relevance. Scope of Review As one of the main factors limiting the accuracy of MD results is the empirical force field used, the present paper offers a review of recent developments in the CHARMM additive force field, one of the most popular bimolecular force fields. Additionally, we present a detailed discussion of the CHARMM Drude polarizable force field, anticipating a growth in the importance and utilization of polarizable force fields in the near future. Throughout the discussion emphasis is placed on the force fields’ parametrization philosophy and methodology. Major Conclusions Recent improvements in the CHARMM additive force field are mostly related to newly found weaknesses in the previous generation of additive force fields. Beyond the additive approximation is the newly available CHARMM Drude polarizable force field, which allows for MD simulations of up to 1 microsecond on proteins, DNA, lipids and carbohydrates. General Significance Addressing the limitations ensures the reliability of the new CHARMM36 additive force field for the types of calculations that are presently coming into routine computational reach while the availability of the Drude polarizable force fields offers a model that is an inherently more accurate model of the underlying physical forces driving macromolecular structures and dynamics.

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Section: The Charmm36 Additive Force Fieldmentioning

confidence: 99%

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

Vanommeslaeghe

MacKerell

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

265

235

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“…Traditionally, only the ground-state, unbiased replica is used for data analysis. 15, 17, 50-51, 62-63 In this study, we propose to combine all the replicas with the weighted histogram analysis method (WHAM) to obtain an optimal distribution under the original potential of the system. Following the original WHAM 64 implementation, the probability distribution from H-REX can be expressed as the combination of the distribution from each replica, 64-65 …”

Section: Theoretical Considerationsmentioning

confidence: 99%

“…9-10 In addition, the variations also impact the 3D conformational properties of these molecules, which has stimulated both experimental and theoretical studies in recent years. 11-17 …”

Section: Introductionmentioning

confidence: 99%

“…49-50 Our previous studies show that H-REX simulations with 1D and 2D biasing potentials applied to the glycosidic linkage dihedrals can greatly enhance conformational sampling for disaccharides and for disaccharides in a glycopeptide. 15, 17 In addition, H-REX has been adopted using a 2D Gaussian-like biasing potential for each linkage in di- and trisaccharides in solution. 51 In the studies in our laboratory the 2D biasing potentials were constructed as the negative of the potential of mean force (PMF) along two linkage dihedrals using the grid-based correction map (CMAP) method, which was originally developed for the protein backbone Φ/Ψ dihedrals in the CHARMM force field.…”

Section: Introductionmentioning

confidence: 99%

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Conformational Sampling of Oligosaccharides Using Hamiltonian Replica Exchange with Two-Dimensional Dihedral Biasing Potentials and the Weighted Histogram Analysis Method (WHAM)

Yang

MacKerell

2015

J. Chem. Theory Comput.

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Oligosaccharides and polysaccharides exert numerous functional roles in biology through their structural diversity and conformational properties. To investigate their conformational properties using computational methods, Hamiltonian replica exchange (H-REX) combined with twodimensional grid-based correction maps as biasing potentials (bpCMAP) significantly improves the sampling efficiency about glycosidic linkages. In the current study, we extend the application of H-REX with bpCMAP to complex saccharides and establish systematic procedures for bpCMAP construction, determination of replica distribution, and data analysis. Our main findings are that (1) the bpCMAP for each type of glycosidic linkage can be constructed from the corresponding disaccharide using gas-phase umbrella sampling simulations, (2) the replica distribution can be conveniently determined following the exact definition of the average acceptance ratio based on the assigned distribution of biasing potentials, and (3) the extracted free energy surface (or potential of mean force (PMF)) can be improved using the weighted histogram analysis method (WHAM) allowing for the inclusion of data from the excited state replicas in the calculated probability distribution. The method is applied to a branched N-glycan found on the HIV gp120 protein, and a linear N-glycan. Considering the general importance of N-glycans and the wide appreciation of the sampling problem, the present method represents an efficient procedure for the conformational sampling of complex oligo-and polysaccharides under explicit solvent conditions. More generally, the use of WHAM is anticipated to be of general utility for the calculation of PMFs from H-REX simulations in a wide range of macromolecular systems.

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“…In order to support the interpretation of the NMR results one would aim at calculating a representative conformational ensemble using molecular dynamics (MD) simulations at room temperature in explicit solvent and compare ensemble statistics of H-H distances with effective NOE distances calculated from relative NOE signal intensities. Despite significant improvements in the development of carbohydrate force fields and in sampling technology like accelerated molecular dynamics [22], replica-exchange molecular dynamics [23][24][25] and Hamiltonian replica-exchange simulation [26][27][28][29], it is still very difficult to generate efficiently and reliably a converged room-temperature ensemble in explicit solvent that provides a basis for reliable interpretation and also to some extent validation of the NMR data. In the case of a discrepancy between the ensemble averaged reff and the effective NOE distance it will remain unclear whether the measured NOE intensity or the simulation results are in question.…”

Section: Resultsmentioning

confidence: 99%

An Unusual Carbohydrate Conformation is Evident in Moraxella catarrhalis Oligosaccharides

et al. 2015

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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 1 H-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, OPEN ACCESSMolecules 2015, 20 14235 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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Conformational Properties of α- or β-(1→6)-Linked Oligosaccharides: Hamiltonian Replica Exchange MD Simulations and NMR Experiments

Cited by 54 publications

References 146 publications

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

Conformational Sampling of Oligosaccharides Using Hamiltonian Replica Exchange with Two-Dimensional Dihedral Biasing Potentials and the Weighted Histogram Analysis Method (WHAM)

An Unusual Carbohydrate Conformation is Evident in Moraxella catarrhalis Oligosaccharides

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