Iduronic acid (IdoA), unlike most other monosaccharides, can adopt different ring conformations, depending on the context of the molecular structure. Accurate modeling of this building block is essential for understanding the role of glycosaminoglycans and other glycoconjugates. Here, we use metadynamics to predict equilibria of (1)C(4), (4)C(1) and (2)S(O) conformations of α-L-IdoA-OMe and α-L-IdoA2S-OMe. Different schemes of scaling of atoms separated by three bonds (1-4 interaction) were tested. It was found that scaling (reduction) of 1-4 electrostatic interactions significantly changes conformational preferences toward the (4)C(1) conformation. More interestingly, scaling of 1-4 van der Waals interaction favors skew-boat conformations. This shows that a minor modification of noncovalent 1-4 interactions parameters can provide a good agreement between populations of conformers of iduronic acid in water from simulations and experiments.

Biased simulations have great potential for the study of slow processes, including protein folding. Atomic motions in molecules are nonlinear, which suggests that simulations with enhanced sampling of collective motions traced by nonlinear dimensionality reduction methods may perform better than linear ones. In this study, we compare an unbiased folding simulation of the Trp-cage miniprotein with metadynamics simulations using both linear (principle component analysis) and nonlinear (Isomap) low dimensional embeddings as collective variables. Folding of the mini-protein was successfully simulated in 200 ns simulation with linear biasing and non-linear motion biasing. The folded state was correctly predicted as the free energy minimum in both simulations. We found that the advantage of linear motion biasing is that it can sample a larger conformational space, whereas the advantage of nonlinear motion biasing lies in slightly better resolution of the resulting free energy surface. In terms of sampling efficiency, both methods are comparable.

Intramolecular hydrogen‐bonding (H‐bonding) is commonly regarded as a major determinant of the conformation of (bio)molecules. However, in an aqueous environment, solvent‐exposed H‐bonds are likely to represent only a marginal (possibly adverse) conformational driving as well as steering force. For example, the hydroxymethyl rotamers of glucose and galactose permitting the formation of an intramolecular H‐bond with the adjacent hydroxyl group are not favored in water but, in the opposite, least populated. This is because the solvent‐exposed H‐bond is dielectrically screened as well as subject to intense H‐bonding competition by the water molecules. In the present study, the effect of a decrease in the solvent polarity on this rotameric equilibrium is probed using molecular dynamics simulation. This is done by considering six physical solvents (H2O, DMSO, MeOH, CHCl3, CCl4, and vacuum), along with 19 artificial water‐like solvent models for which the dielectric permittivity and H‐bonding capacity can be modulated independently via a scaling of the O–H distance and of the atomic partial charges. In the high polarity solvents, the intramolecular H‐bond is observed, but arises as an opportunistic consequence of the proximity of the H‐bonding partners in a given rotameric state. Only when the polarity of the solvent is decreased does the intramolecular H‐bond start to induce a conformational pressure on the rotameric equilibrium. The artificial solvent series also reveals that the effects of the solvent permittivity and of its H‐bonding capacity mutually enhance each other, with a slightly larger influence of the permittivity. The hydroxymethyl conformation in hexopyranoses appears to be particularly sensitive to solvent‐polarity effects because the H‐bond involving the hydroxymethyl group is only one out of up to five H‐bonds capable of forming a network around the ring.

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