Impact of Polarization on the Ring Puckering Dynamics of Hexose Monosaccharides.

Analysis of crystal structures of hexose monosaccharides α-d-mannose (α-MAN), ß-d-mannose (ß-MAN), α-d-glucose (α-GLC), ß-d-glucose (ß-GLC), α-d-galactose (α-GAL), ß-d-galactose (ß-GAL), α-d-altrose (α-ALT), ß-d-altrose (ß-ALT), α-d-idose (α-IDO), and ß-d-idose (ß-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.

Classification of the human THAP protein family identifies an evolutionarily conserved coiled coil region.

BACKGROUND: The THAP (Thanatos Associated Proteins) protein family in humans is implicated in various important cellular processes like epigenetic regulation, maintenance of pluripotency, transposition and disorders like cancers and hemophilia. The human THAP protein family which consists of twelve members of different lengths has a well characterized amino terminal, zinc-coordinating, DNA-binding domain called the THAP domain. However, the carboxy terminus of most THAP proteins is yet to be structurally characterized. A coiled coil region is known to help in protein oligomerization in THAP1 and THAP11. It is not known if other human THAP proteins oligomerize. We have used bioinformatic tools to explore the possibility of dimerization of THAP proteins via a coiled coil region. RESULTS: Classification of human THAP protein into three size based groups led to the identification of an evolutionarily conserved alpha helical region, downstream of the amino terminal THAP domain. Secondary structure predictions, alpha helical wheel plots and protein models demonstrated the strong possibility of coiled coil formation in this conserved, leucine rich region of all THAP proteins except THAP10. CONCLUSIONS: The identification of a predicted oligomerization region in the human THAP protein family opens new directions to investigate the members of this protein family.

Correction to: Classification of the human THAP protein family identifies an evolutionarily conserved coiled coil region.

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Elucidating the role of key structural motifs in antifreeze glycoproteins.

Antifreeze glycoproteins (AFGPs) are distinctively riveting class of bio-macromolecules, which endows the survival of organisms inhabiting polar and subpolar regions. These proteins are believed to hinder microscopic freezing by interacting with embryonic ice crystals and precluding their further growth. The underlying molecular mechanism by which AFGPs bind to ice has remained elusive due to insufficient structural characterization, with conflicting hypotheses on the possible binding mode of AFGPs - either via the hydrophobic peptide backbone or via the hydrophilic carbohydrate side chains - when interacting with ice. Chemical synthesis has allowed researchers to access synthetic variants of natural AFGPs. These studies revealed that AFGPs exhibit huge variations in their thermal hysteresis and ice shaping behavior with only slight structural variations, especially to the carbohydrate side chains. Four key structural motifs were identified as crucial to AFGP activity: the presence of a threonine γ-methyl group, an α-glycosidic carbohydrate-protein linkage, an acetylamide group (-NHCOCH3) at the C2 position of the carbohydrate linked to the protein, and the presence of carbohydrate hydroxyl groups. In this study, we use molecular dynamics (MD) simulations to probe the microscopic properties of water accompanying these structural variations of AFGPs. We find that these variations primarily influence the conformation space of AFGPs and also crucially control their hydration dynamics. Owing to the disordered nature of AFGPs we use Markov-state modeling to identify the conformational preferences of AFGPs. The simulations reveal the importance of steric bulk, intra-molecular carbohydrate-protein H-bonds and conformational preferences (α- vs. ß-linkages) in controlling the spatial segregation of the hydrophilic and hydrophobic regions of AFGPs. We hypothesize that the hydrophobic component of AFGPs is crucial to their binding to ice, which determines the ice shaping ability of AFGPs. However, the hydrophilic carbohydrate hydroxyl groups and their ability to form water bridges control the subsequent hydration dynamics, which is key to the antifreeze properties. Investigating the tetrahedral order parameter of water molecules around the carbohydrates revealed competition between solute- and bulk-influenced solvent structures, with maximum restructuring being observed in the interfacial region 2.5-4.5 Å away from the AFGPs.

KELM-CPPpred: Kernel Extreme Learning Machine Based Prediction Model for Cell-Penetrating Peptides.

Cell-penetrating peptides (CPPs) facilitate the transport of pharmacologically active molecules, such as plasmid DNA, short interfering RNA, nanoparticles, and small peptides. The accurate identification of new and unique CPPs is the initial step to gain insight into CPP activity. Experiments can provide detailed insight into the cell-penetration property of CPPs. However, the synthesis and identification of CPPs through wet-lab experiments is both resource- and time-expensive. Therefore, the development of an efficient prediction tool is essential for the identification of unique CPP prior to experiments. To this end, we developed a kernel extreme learning machine (KELM) based CPP prediction model called KELM-CPPpred. The main data set used in this study consists of 408 CPPs and an equal number of non-CPPs. The input features, used to train the proposed prediction model, include amino acid composition, dipeptide amino acid composition, pseudo amino acid composition, and the motif-based hybrid features. We further used an independent data set to validate the proposed model. In addition, we have also tested the prediction accuracy of KELM-CPPpred models with the existing artificial neural network (ANN), random forest (RF), and support vector machine (SVM) approaches on respective benchmark data sets used in the previous studies. Empirical tests showed that KELM-CPPpred outperformed existing prediction approaches based on SVM, RF, and ANN. We developed a web interface named KELM-CPPpred, which is freely available at http://sairam.people.iitgn.ac.in/KELM-CPPpred.html.

Insight into Early-Stage Unfolding of GPI-Anchored Human Prion Protein.

Prion diseases are fatal neurodegenerative disorders, which are characterized by the accumulation of misfolded prion protein (PrPSc) converted from a normal host cellular prion protein (PrPC). Experimental studies suggest that PrPC is enriched with α-helical structure, whereas PrPSc contains a high proportion of ß-sheet. In this study, we report the impact of N-glycosylation and the membrane on the secondary structure stability utilizing extensive microsecond molecular dynamics simulations. Our results reveal that the HB (residues 173 to 194) C-terminal fragment undergoes conformational changes and helix unfolding in the absence of membrane environments because of the competition between protein backbone intramolecular and protein-water intermolecular hydrogen bonds as well as its intrinsic instability originated from the amino acid sequence. This initiation of the unfolding process of PrPC leads to a subsequent increase in the length of the HB-HC loop (residues 195 to 199) that may trigger larger rigid body motions or further unfolding around this region. Continuous interactions between prion protein and the membrane not only constrain the protein conformation but also decrease the solvent accessibility of the backbone atoms, thereby stabilizing the secondary structure, which is enhanced by N-glycosylation via additional interactions between the N-glycans and the membrane surface.

Transmembrane domain II of the human bile acid transporter SLC10A2 coordinates sodium translocation.

Human apical sodium-dependent bile acid transporter (hASBT, SLC10A2) is responsible for intestinal reabsorption of bile acids and plays a key role in cholesterol homeostasis. We used a targeted and systematic approach to delineate the role of highly conserved transmembrane helix 2 on the expression and function of hASBT. Cysteine mutation significantly depressed transport activity for >60% of mutants without affecting cell surface localization of the transporter. All mutants were inaccessible toward chemical modification by membrane-impermeant MTSET reagent, strongly suggesting that transmembrane 2 (TM2) plays an indirect role in bile acid substrate translocation. Both bile acid uptake and sodium dependence of TM2 mutants revealed a distinct α-helical periodicity. Kinetic studies with conservative and non-conservative mutants of sodium sensitive residues further underscored the importance of Gln(75), Phe(76), Met(79), Gly(83), Leu(86), Phe(90), and Asp(91) in hASBT function. Computational analysis indicated that Asp(91) may coordinate with sodium during the transport cycle. Combined, our data propose that a consortium of sodium-sensitive residues along with previously reported residues (Thr(134), Leu(138), and Thr(149)) from TM3 may form the sodium binding and translocation pathway. Notably, residues Gln(75), Met(79), Thr(82), and Leu(86) from TM2 are highly conserved in TM3 of a putative remote bacterial homologue (ASBTNM), suggesting a universal mechanism for the SLC10A transporter family.

Conformational determinants of the activity of antiproliferative factor glycopeptide.

The antiproliferative factor (APF) involved in interstitial cystitis is a glycosylated nonapeptide (TVPAAVVVA) containing a sialylated core 1 α-O-disaccharide linked to the N-terminal threonine. The chemical structure of APF was deduced using spectroscopic techniques and confirmed using total synthesis. The synthetic APF provided a platform to study amino acid modifications and their effect on APF activity, based on which a structure-activity relationship (SAR) for APF activity was previously proposed. However, this SAR model could not explain the change in activity associated with minor alterations in the peptide sequence. Presented is computational analysis of 14 APF derivatives to identify structural trends from which a more detailed SAR is obtained. The APF activity is found to be dictated by the close interplay between carbohydrate-peptide and peptide-peptide interactions. The former involves hydrogen bond and hydrophobic interactions, and the latter is dominated by hydrophobic interactions. The highly flexible hydrophobic peptide adopts collapsed conformations separated by low energy barriers. APF activity correlates with hydrophobic clustering associated with amino acids 4A, 6V, and 8V. Peptide conformations are highly sensitive to single point mutations, which explain the experimental trends. The presented SAR will act as a guide for lead optimization of more potent APF analogues of potential therapeutic utility.

Unveiling DNA Translocation in Pristine Graphene Nanopores: Understanding Pore Clogging via Polarizable Simulations.

Graphene has garnered remarkable attention in recent years as an attractive nanopore membrane for rapid and accurate sequencing of DNA. The inherent characteristics of graphene offer exquisite experimental control over pore dimensions, encompassing both the width (pore diameter) and height. Despite these promising prospects, the practical deployment of pristine graphene nanopores for DNA sequencing has encountered a formidable challenge in the form of pore clogging, which is primarily attributed to hydrophobic interactions. However, a comprehensive understanding of the atomistic origins underpinning this clogging phenomenon and the nuanced impact of individual nucleobase identities on clogging dynamics remain an underexplored domain. Elucidating the atomistic intricacies governing pore clogging is pivotal to devising strategies for its mitigation and advancing our understanding of graphene nanopore behavior. We harness Drude polarizable simulations to systematically dissect the nucleobase-dependent mechanisms that play a pivotal role in nanopore clogging. We unveil nucleobase-specific interactions that illuminate the multifaceted roles played by both hydrophobic and electrostatic forces in driving nanopore clogging events. Notably, the Drude simulations also unveil the bias-dependent translocation dynamics and its pivotal role in alleviating pore clogging─a facet that remains significantly underestimated in conventional additive (nonpolarizable) simulations. Our findings underscore the indispensability of incorporating polarizability to faithfully capture the intricate dynamics governing graphene nanopore translocation phenomena, thus deepening our insights into this crucial field.

Capturing charge and size effects of ions at the graphene-electrolyte interface using polarizable force field simulations.

We present a systematic investigation capturing the charge and size effects of ions interacting with a graphene surface using polarizable simulations. Our results utilizing the Drude polarizable force field (FF) for ions, water and graphene surfaces, show that the graphene parameters previously developed by us are able to accurately capture the dynamics at the electrolyte-graphene interface. For monovalent ions, with increasing size, the solvation shell plays a crucial role in controlling the ion-graphene interactions. Smaller monovalent ions directly interact with the graphene surface, while larger ions interact with the graphene surface via a well-formed solvation shell. For divalent ions, both interaction modes are observed. For the anion Cl-, we observe direct interaction between the ions and the graphene surface. The anion-graphene interactions are strongly driven by the polarizability of the graphene surface. These effects are not captured in the absence of polarization by additive FF simulations. The present study underlines the importance of polarizability in capturing the interfacial phenomenon at the solid-solute interface.

Experimental and simulation studies reveal mechanism of action of human defensin derivatives.

Antimicrobial peptides (AMPs) are naturally occurring promising candidates which can be used as antibiotics against a wide variety of bacteria. The key component for using them as a potent antibiotic is that their mechanism of action is less prone to bacterial resistance. However, the molecular details of their mechanism of action is not yet fully understood. In this study, we try to shed light on the mode of action of AMPs, possible reason behind it, and their interaction with lipid bilayers through experimental as well as molecular dynamics (MD) simulation studies. The focal of our study was Human beta defensin 3 (hBD-3) which is a naturally occurring AMP. We chose three derivatives of hBD-3, namely CHRG01, KSR, and KLR for the detailed analysis presented in this study. These three peptides are evaluated for their antibacterial potency, secondary structure analysis and mechanism of action. The experimental results reveal that these peptides are active against gram positive as well as gram negative bacteria and kill bacteria by forming membrane pores. The MD simulation results correlate well with the antibacterial activity and shed light into the early membrane insertion dynamics. Moreover, the specific amino acids responsible for membrane disruptions are also identified from the MD simulations. Understanding the molecular level interaction of individual amino acids with the lipid bilayer will greatly help in the design of more efficient antimicrobial peptides.

Phosphorylation-Induced Structural Reorganization in Tau-Paired Helical Filaments.

Taupathies involve the deposition of abnormal tau protein into neurofibrillary tangles (NFTs) in the human brain. The abnormally hyperphosphorylated tau dissociates from microtubules and forms insoluble aggregates known as paired helical filaments (PHFs), highlighting the importance of post-translational modifications in taupathies. The present study examines the factors responsible for the structural stability of PHFs in native as well as in phosphorylated and O-GlcNAcylated tau. We carried out molecular dynamics simulations on the R3-R4 repeat domains of the human tau protein to gain atomic insights into the key noncovalent interactions responsible for their unique dimeric C-shaped structure. The structural effects upon post-translational modification were found to be prominent for phosphorylation when compared with O-GlcNAcylation. O-GlcNAcylated tau was found to retain the "C conformation" observed in the native tau PHF, whereas upon phosphorylation, we observed a conformational transition to a more opened "H conformation". We found that this conformational transition is brought about by the loss of a key salt bridge between Lys353 and Asp358 due to the phosphorylation at Ser356 that results in the reorganization of the dimeric interface.

Site-Specific Stabilization and Destabilization of α Helical Peptides upon Phosphorylation and O-GlcNAcylation.

Helices (α-helix) are the most common type of secondary structure motif present in proteins. In this study, we have investigated the structural influence of phosphorylation and O-GlcNAcylation, common intracellular post-translational modifications (PTMs), on the α-helical conformation. The simulation studies were performed on the Baldwin model α-helical peptide sequence (Ac-AKAAAAKAAAAKAA-NH2). The Baldwin sequences were chosen due to the availability of site-specific experimental post-translational data for cross-validation with the simulations. The influence of PTMs was examined across the span of the α-helix, namely, at the N-terminus, position 10 (interior region), and the C-terminus for both serine and threonine residues placed at these positions. Molecular dynamics (MD) simulations revealed that phosphorylation and O-GlcNAcylation at the N-terminus lead to the stabilization of the helical conformation. PTMs in the interior or the C-terminus were found to disrupt helicity, with the disruption being more pronounced for PTMs in the interior region, in accordance with experimental studies. It was found that phosphorylation-derived destabilization was mainly due to the formation of an intraresidue HN-PO32- electrostatic interaction and interactions between the phosphate group and the side chain of adjacent lysine residues (NH3···PO32-). Hydrophobic and steric clashes were the main causes of destabilization in the case of O-GlcNAcylation. The structural disruptions were found to be more pronounced for PTM at the threonine site when compared to the serine site. The salt-bridge-dependent stability of the α-helix was found to be highly position specific, an i → i + 4 interaction stabilizing the helix, with other placements leading to the destabilization of the helix.

Polarization influences the evolution of nucleobase-graphene interactions.

In recent years, graphene has attracted attention from researchers as an atomistically thin solid state material for the study on the self-assembly of nucleobases. Non-covalent interactions between nucleobases and graphene sheets play a fundamental role in understanding the self-assembly of nucleobases on the graphene sheet. A fundamental understanding of the effect of molecular polarizability on these non-covalent interactions between the nucleobases and the underlying graphene sheet is absent in the literature. In this paper, we present the results from polarizable molecular dynamics simulation studies to understand the effect of polarization on the strength of non-covalent interactions. To this end, we report the development of Drude parameters for describing the polarizable graphene sheet. The developed parameters were used to study the self-aggregation phenomenon of nucleobases on a graphene support. We observe a significant change in the interaction patterns upon the inclusion of polarization into the system, with polarizable simulations yielding results that closely resemble the experimental studies. Two of the key observations were the probability of the formation of stacks in guanine-rich systems, and the spontaneous formation of H-bonded structures over the graphene sheet, which allude to the importance of the DNA sequence and composition. Both these effects were not observed in the additive simulations. The present study sheds light on the effect of polarization on the adsorption of DNA nucleobases on a graphene sheet, but the methodology can be extended to include a variety of small molecules and complete DNA strands.

Effect of Phosphorylation and O-GlcNAcylation on Proline-Rich Domains of Tau.

The microtubule-associated protein Tau (MAPT) is a phosphoprotein in neurons of the brain. Aggregation of Tau is the leading cause of tauopathies such as Alzheimer's disease. Tau undergoes several post-translational modifications of which phosphorylation and O-GlcNAcylation are key chemical modifications. Tau aggregates into paired helical filaments and neurofibrillary tangles upon hyperphosphorylation, whereas O-GlcNAcylation stabilizes the soluble form of Tau. How specific phosphorylation and/or O-GlcNAcylation events influence Tau conformations remains largely unknown due to the disordered nature of Tau. In this study, we have investigated the phosphorylation- and O-GlcNAcylation-induced conformational effects on a Tau segment (Tau225-246) from the proline-rich domain (P2), by performing metadynamics simulations. We study two different phosphorylation patterns: Tau225-246, phosphorylated at T231 and S235, and Tau225-246, phosphorylated at T231, S235, S237, and S238. We also study O-GlcNAcylation at T231 and S235. We find that phosphorylation leads to the formation of strong salt-bridge contacts with adjacent lysine and arginine residues, which disrupts the native ß-sheet structure observed in Tau225-246. We also observe the formation of a transient α-helix (238SAKSRLQ244) when Tau225-246 is phosphorylated at four sites. In contrast, O-GlcNAcylation shows only modest structural effects, and the resultant structure resembles the native form of the peptide. Our studies suggest the opposing structural effects of both protein post-translational modifications (PTMs) and the importance of salt bridges in governing the conformational preferences upon phosphorylation, highlighting the role of proximal arginine and lysine upon hyperphosphorylation.

Relationship of intertwin crown-rump length discrepancy to chorionicity, fetal demise and birth-weight discordance.

OBJECTIVES: To study the frequency and clinical significance of crown-rump length (CRL) discrepancy at 11-14 weeks of gestation in twin pregnancies from an unselected population. METHODS: This was a retrospective analysis of all twin pregnancies that underwent a routine 11-14-week scan at a large teaching hospital. Fetal loss was defined as fetal demise of one or both twins after 14 weeks. RESULTS: A total of 507 twin pregnancies were studied; 382 (75.3%) were dichorionic and 125 (24.7%) were monochorionic twins. The discrepancy in CRL was expressed as a percentage of the CRL of the larger twin. The 95(th) and 99(th) centile for CRL discrepancy in twins was 12.2% and 19.3%, respectively. The discrepancy in CRLs in monochorionic and dichorionic twins was not significantly different (Mann-Whitney U = 22,406, P = 0.302). In 39 twin pairs, there was subsequent intrauterine death of one or both twins. Fetal loss was more common in monochorionic twins (24/125) than in dichorionic twins (15/382) (chi-square = 30.9, P < 0.001). In monochorionic twins, the discrepancy in CRLs in the 24 cases with subsequent loss was significantly greater than in the 101 twin pairs with no subsequent loss (Mann-Whitney U = 896, P = 0.048). The discrepancy in CRLs in 15 dichorionic twins with subsequent loss was not different from that in the 367 twins with no loss (Mann-Whitney U = 2116.5, P = 0.129). The CRL discrepancy was significantly correlated with birth-weight discordance in twins (Spearman's rho = 0.128, P = 0.006). However, this was due to a significant correlation in dichorionic twins (Spearman's rho = 0.127, P = 0.016) but not in monochorionic twins (Spearman's rho = 0.145, P = 0.14). CONCLUSIONS: Fetal loss is significantly associated with discrepancy in CRL at the 11-14-week scan in monochorionic twins and discordance in birth weights is significantly associated with discrepancy in CRL in dichorionic twins. However, intertwin CRL discrepancy is of limited value in screening for these adverse events.

Impact of audit of routine second-trimester cardiac images using a novel image-scoring method.

OBJECTIVE: To assess the impact of using an objective scoring method to audit cardiac images obtained as part of the routine 21-23-week anomaly scan. METHODS: A prospective audit and re-audit (6 months later) were conducted on cardiac images obtained by sonographers during the routine anomaly scan. A new image-scoring method was devised based on expected features in the four-chamber and outflow tract views. For each patient, scores were awarded for documentation and quality of individual views. These were called 'Documentation Scores' and 'View Scores' and were added to give a 'Patient Score' which represented the quality of screening provided by the sonographer for that particular patient (maximum score, 15). In order to assess the overall performance of sonographers, an 'Audit Score' was calculated for each by averaging his or her Patient Scores. In addition, to assess each sonographer's performance in relation to particular aspects of the various views, each was given their own 'Sonographer View Scores', derived from image documentation and details of four-chamber view (magnification, valve offset and septum) and left and right outflow tract views. All images were scored by two reviewers, jointly in the primary audit and independently in the re-audit. The scores from primary and re-audit were compared to assess the impact of feedback from the primary audit. RESULTS: Eight sonographers participated in the study. The median Audit Score increased significantly (P < 0.01), from 10.8 (range, 9.8-12.4) in the primary audit to 12.4 (range, 10.4-13.6) in the re-audit. Scores allocated by the two reviewers in the re-audit were not significantly different (P = 0.08). CONCLUSION: Objective scoring of fetal heart images is feasible and has a positive impact on the quality of cardiac images acquired at the time of the routine anomaly scan. This audit tool has the potential to be applied in every obstetric scanning unit and may improve the effectiveness of screening for congenital heart defects.

Fluctuations at the base pair level effecting charge transfer in DNA.

We investigate the energetics of the basepair degrees of freedom and their effects on the overall charger transfer processes in DNA. We find that the rotational and translational basepair degrees of freedom can be broadly classified into soft and hard vibrational modes, with the stiffness of the modes depending on the nature of the basepair. We also find that the intrabasepair charge transfer, in the A:T and G:C basepairs, is strongly influenced by open (sigma) and stretch (Sy) vibrational modes. Our calculations for the AT-GC and GC-AT dinucleotide steps suggest that the fluctuations in the G:C basepair strongly influence the site energies when compared to fluctuations in the A:T basepair. However, for both the dinucleotide steps, we find that the charge transfer integrals are strongly influenced by the fluctuations at the basepair level. Overall, our studies suggest that for a better understanding of the overall charge transfer processes, it is important to account for the basepair fluctuations.

Conformational tuning of magnetic interactions in metal-DNA complexes.

The alignment of Cu(2+) ions along a modified DNA helix is studied with either hydroxypyridone (H) or bis(salicylaldehyde)ethylenediamine (S-en) metalated base pairs (MBPs). The conformational motion of H-MBP leads to the interlinking of the H-MBPs by an extended Cu-O network that is ferromagnetic, whereas the conformational freezing of the S-en-MBP leads to an ordered pairwise-stacked arrangement that is weakly antoferrimagnetic.

Drude Polarizable Force Field Parametrization of Carboxylate and N-Acetyl Amine Carbohydrate Derivatives.

In this work, we report the development of Drude polarizable force field parameters for the carboxylate and N-acetyl amine derivatives, extending the functionality of the existing Drude polarizable carbohydrate force field. The force field parameters have been developed in a hierarchical manner, reproducing the quantum mechanical gas-phase properties of small model compounds representing the key functional group in the carbohydrate derivatives, including optimization of the electrostatic and bonded parameters. The optimized parameters were then used to generate the models for carboxylate and N-acetyl amine carbohydrate derivatives. The transferred parameters were further tested and optimized to reproduce crystal geometries and J-coupling data from nuclear magnetic resonance experiments. The parameter development resulted in the incorporation of d-glucuronate, l-iduronate, N-acetyl-d-glucosamine (GlcNAc), and N-acetyl-d-galactosamine (GalNAc) sugars into the Drude polarizable force field. The parameters developed in this study were then applied to study the conformational properties of glycosaminoglycan polymer hyaluronan, composed of d-glucuronate and N-acetyl-d-glucosamine, in aqueous solution. Upon comparing the results from the additive and polarizable simulations, it was found that the inclusion of polarization improved the description of the electrostatic interactions observed in hyaluronan, resulting in enhanced conformational flexibility. The developed Drude polarizable force field parameters in conjunction with the remainder of the Drude polarizable force field parameters can be used for future studies involving carbohydrates and their conjugates in complex, heterogeneous systems.