Impact of Polarization on the Ring Puckering Dynamics of Hexose Monosaccharides

Abstract

Analysis of crystal structures of hexose monosaccharides α-d-mannose (α-MAN), β-d-mannose (β-MAN), α-d-glucose (α-GLC), β-d-glucose (β-GLC), α-d-galactose (α-GAL), β-d-galactose (β-GAL), α-d-altrose (α-ALT), β-d-altrose (β-ALT), α-d-idose (α-IDO), and β-d-idose (β-IDO) reveals that the monosaccharide ring adopts multiple ring conformations. These ring conformations can be broadly classified as chair, half-chair, envelope, boat, and skew-boat conformations. The ability of the monosaccharide ring to adopt multiple conformations has been closely tied with their bioactivity. However, it has been difficult to capture the dynamic information of these conformations from experimental studies. Even from simulations, capturing these different conformations is challenging because of the energy barriers involved in the transitions between the stable 4C1 and 1C4 chair forms. In this study, we analyze the influence of the polarizable force field on the ring dynamics of five major types of unsubstituted aldohexosesglucose, mannose, galactose, altrose, and idoseand their anomers. We simulate microsecond trajectories to capture the influence of the CHARMM36 additive and polarizable carbohydrate force fields on the ring dynamics. The microsecond trajectories allow us to comment on the issues associated with equilibrium molecular dynamics simulations. Further, we use the extended system adaptive biasing force (eABF) method to compare the conformational sampling efficiencies of the additive and polarizable force fields. Our studies reveal that inclusion of polarization enhances the sampling of ring conformations and lowers the energy barriers between the 4C1 and 1C4 conformations. Overall, the CHARMM36 additive force field is observed to be rigid and favor the 4C1 conformations. Although the inclusion of polarizability results in enhancing ring flexibility, we observe sampling that does not agree with experimental results, warranting a revision of the polarizable Drude parameters.

Glycan Shape, Motions, and Interactions Explored by NMR Spectroscopy

“…However, sampling conformational space and investigation of ring puckering for d -hexopyranoses show that the CARMM36 additive force field tends to overstabilize the 4 C 1 conformation, whereas the Drude polarizable carbohydrate force field results in flexible ring systems, more readily accessible skew and boat conformations, lower free energy barriers, and oversampling of the 1 C 4 conformation for some of the monosaccharides. 26 The inverted 1 C 4 conformation for α- d -mannopyranose was in these MD simulations present to an extent of ∼80%, whereas in a study of α-linked d -mannopyranose disaccharides using the Drude polarizable force field a wider conformational sampling at glycosidic linkages was evident, without any oversampling of inverted chairs. 27 Even though sampling of conformational space by MD simulations using the Drude model is ∼4-fold slower than the additive CHARMM force field, and ∼8-fold slower than using a hydrogen mass repartitioning (HMR) approach by increasing the mass of hydrogen by distributing a heavy atom mass to hydrogen atom(s) attached to the heavy atom, 28 the modeling is performed in a more realistic way, for glycans per se but in particular for understanding and unveiling the structural basis of ligand recognition and specificity in carbohydrate–protein interactions, which calls for further developments of the Drude polarizable force fields.…”

“…A remedy for this is, among others, the classical Drude oscillator model, also known as the “charge-on-spring model”, in which explicit polarization is implemented by attaching a charged auxiliary particle with a harmonic spring to the core of the polarizable atom, thereby allowing for the atomic dipoles to adjust in response to the surrounding electric field. However, sampling conformational space and investigation of ring puckering for d -hexopyranoses show that the CARMM36 additive force field tends to overstabilize the 4 C 1 conformation, whereas the Drude polarizable carbohydrate force field results in flexible ring systems, more readily accessible skew and boat conformations, lower free energy barriers, and oversampling of the 1 C 4 conformation for some of the monosaccharides . The inverted 1 C 4 conformation for α- d -mannopyranose was in these MD simulations present to an extent of ∼80%, whereas in a study of α-linked d -mannopyranose disaccharides using the Drude polarizable force field a wider conformational sampling at glycosidic linkages was evident, without any oversampling of inverted chairs .…”

sAMP-VGG16: Drude polarizable force-field assisted image-based deep neural network prediction model for short antimicrobial peptides

“…The Drude polarizable FF [36][37][38] is a well-known atomistic FF is well-established atomistic FF that incorporates classical Drude oscillators to accommo-date electronic polarization. The Drude polarizable FF parameters have been meticulously optimized to model biological systems, such as proteins [39][40][41][42], lipid [43][44][45], nucleic acids [46][47][48], carbohydrates [49][50][51][52], ions [45,53], and small molecules [54][55][56] incorporated in the systems. In this study, the Drude atom type and their connectivity information were used to generate input features for sAMP prediction model.…”