Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the 4C1 form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p

Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the ⁴C₁ form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p

Size-Tunable Trehalose-Based Nanocavities: Synthesis, Structure, and Inclusion Properties of Large-Ring Cyclotrehalans

13 páginas, 4 figuras, 1 tabla, esquemas.An efficient strategy toward the synthesis of large-ring cyclodextrin (CD) analogs alternating alpha,alpha'-trehalose disaccharide subunits and pseudoamide segments (cyclotrehalans, CTs), involving a bimolecular macrocyclization reaction as the key step, is reported. NMR and molecular modeling confirmed that the eight and ten alpha-d-glucopyranoside subunits in tetrameric and pentameric CT homologues (CT4 and CT5, respectively) are magnetically equivalent, as in the gamma and epsilonCD counterparts. Yet, the orientation of the monosaccharide constituents is reversed in CTs as compared with CDs, the beta-face being directed to the inside of the nanometric cavity while the alpha-face remains in contact with the bulk solvent. Molecular mechanics and dynamics experiments revealed that the cyclooligosaccharide architecture in CT4 and CT5 is relatively flexible, which is in contrast to that previously observed for the first members of the CT series (CT2 and CT3 oligomers). Thus, although in their fully expanded conformation their cavity size is close to that of gammaCD, the higher mobility of the pseudoamide bridges as compared with classical glycosidic linkages endows these hosts with induced fitting capabilities toward smaller guests.We thank the Spanish Ministerio de Educación y Ciencia (contract numbers CTQ2006-15515-C02-01/BQU, CTQ2007-61180/PPQ, and CTQ2006-08256 and a doctoral fellowship to D.R.-L.) and the Junta de Andalucía.Peer reviewe

Exploring Protein Kinase Conformation Using Swarm-Enhanced Sampling Molecular Dynamics

Protein plasticity, while often linked to biological function, also provides opportunities for rational design of selective and potent inhibitors of their function. The application of computational methods to the prediction of concealed protein concavities is challenging, as the motions involved can be significant and occur over long time scales. Here we introduce the swarm-enhanced sampling molecular dynamics (sesMD) method as a tool to improve sampling of conformational landscapes. In this approach, a swarm of replica simulations interact cooperatively via a set of pairwise potentials incorporating attractive and repulsive components. We apply the sesMD approach to explore the conformations of the DFG motif in the protein p38α mitogen-activated protein kinase. In contrast to multiple MD simulations, sesMD trajectories sample a range of DFG conformations, some of which map onto existing crystal structures. Simulated structures intermediate between the DFG-in and DFG-out conformations are predicted to have druggable pockets of interest for structure-based ligand design

Secondary Structure of Short β‑Peptides as the Chiral Expression of Monomeric Building Units: A Rational and Predictive Model

Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The <i>cis</i>-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the <i>trans</i>-form manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers. A lego-type molecular architecture evolves; the overall look depends only on the conformational properties of the structural building units. A versatile and efficient method to predict the backbone folds of designed cyclobutane β-peptides is based on QM calculations. Predictions are corroborated by high-resolution NMR studies on selected stereoisomers, most of them being new foldamers that have been synthesized and characterized for the first time. Thus, the chiral expression of monomeric building units results in the defined secondary structures of small oligomers. As a result of this study, a new set of chirality controlled foldamers is provided to probe as biocompatible biopolymers