Refinement of the Drude Polarizable Force Field for Hexose Monosaccharides: Capturing Ring Conformational Dynamics with Enhanced Accuracy.

We present a revised version of the Drude polarizable carbohydrate force field (FF), focusing on refining the ring and exocyclic torsional parameters for hexopyranose monosaccharides. This refinement addresses the previously observed discrepancies between calculated and experimental NMR coupling values, particularly in describing ring dynamics and exocyclic rotamer populations within major hexose monosaccharides and their anomers. Specifically, α-MAN, β-MAN, α-GLC, β-GLC, α-GAL, β-GAL, α-ALT, β-ALT, α-IDO, and β-IDO were targeted for optimization.

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.

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.

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

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.

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-NH).

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.

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 -GlcNAcylated tau.

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.

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.

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

In this work, we report the development of Drude polarizable force field parameters for the carboxylate and -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 -acetyl amine carbohydrate derivatives.

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.

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.

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.

Phosphorylation versus O-GlcNAcylation: Computational Insights into the Differential Influences of the Two Competitive Post-Translational Modifications.

Phosphorylation and O-GlcNAcylation are rapidly cycling intracellular protein post-translational modifications (PTMs) that can compete for the same serine (S) and threonine (T) sites. Limited crystal structure information is available on the direct influence of these PTMs on the underlying protein structure, especially for O-GlcNAcylation. NMR and CD studies show that these competitive-PTMs can have the same or differential influence on the overall secondary structure.

Influence of Polarization on Carbohydrate Hydration: A Comparative Study Using Additive and Polarizable Force Fields.

Carbohydrates are known to closely modulate their surrounding solvent structures and influence solvation dynamics. Spectroscopic investigations studying far-IR regions (below 1000 cm(-1)) have observed spectral shifts in the libration band (around 600 cm(-1)) of water in the presence of monosaccharides and polysaccharides. In this paper, we use molecular dynamics simulations to gain atomistic insight into carbohydrate-water interactions and to specifically highlight the differences between additive (nonpolarizable) and polarizable simulations.

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 β-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.

Molecular dynamics simulations of glycoproteins using CHARMM.

Molecular dynamics simulations are an effective tool to study the structure, dynamics, and thermodynamics of carbohydrates and proteins. However, the simulations of heterogeneous glycoprotein systems have been limited due to the lack of appropriate molecular force field parameters describing the linkage between the carbohydrate and the protein regions as well as the tools to prepare these systems for modeling studies. In this work we outline the recent developments in the CHARMM carbohydrate force field to treat glycoproteins and describe in detail the step-by-step procedures involved in building glycoprotein geometries using CHARMM-GUI Glycan Reader.

Perturbation of long-range water dynamics as the mechanism for the antifreeze activity of antifreeze glycoprotein.

Very little is known about the mechanism of antifreeze action of antifreeze glycoproteins (AFGPs) present in Antarctic teleost fish. Recent NMR and CD studies assisted with total synthesis of synthetic AFGP variants have provided insight into the structure of short AFGP glycopeptides, though the observations did not yield information on the antifreeze mechanism of action. In this study, we use Hamiltonian replica exchange (HREX) molecular dynamics simulations to probe the structure and surrounding aqueous environments of both the natural (AFGP8) and synthetic (s-AFGP4) AFGPs.

Conformational properties of α- or β-(1→6)-linked oligosaccharides: Hamiltonian replica exchange MD simulations and NMR experiments.

Conformational sampling for a set of 10 α- or β-(1→6)-linked oligosaccharides has been studied using explicit solvent Hamiltonian replica exchange (HREX) simulations and NMR spectroscopy techniques. Validation of the force field and simulation methodology is done by comparing calculated transglycosidic J coupling constants and proton-proton distances with the corresponding NMR data. Initial calculations showed poor agreement, for example, with >3 Hz deviation of the calculated (3)J(H5,H6R) values from the experimental data, prompting optimization of the ω torsion angle parameters associated with (1→6)-linkages.

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.

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.

CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates.

Presented is an extension of the CHARMM additive all-atom carbohydrate force field to enable the modeling of phosphate and sulfate linked to carbohydrates. The parameters are developed in a hierarchical fashion using model compounds containing the key atoms in the full carbohydrates. Target data for parameter optimization included full two-dimensional energy surfaces defined by the glycosidic dihedral angle pairs in the phosphate/sulfate model compound analogs of hexopyranose monosaccharide phosphates and sulfates, as determined by quantum mechanical (QM) MP2/cc-pVTZ single point energies on MP2/6-31+G(d) optimized structures.

CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling.

Monosaccharide derivatives such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details development of force-field parameters for these monosaccharides and their covalent connections to proteins via O-linkages to serine or threonine sidechains and via N-linkages to asparagine sidechains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small molecules.

Influence of solvent and intramolecular hydrogen bonding on the conformational properties of o-linked glycopeptides.

A detailed investigation of the conformational properties of all the biologically relevant O-glycosidic linkages using the Hamiltonian replica exchange (HREX) simulation methodology and the recently developed CHARMM carbohydrate force field parameters is presented. Fourteen biologically relevant O-linkages between the five sugars N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), D-glucose (Glc), D-mannose (Man), and L-fucose (Fuc) and the amino acids serine and threonine were studied. The force field was tested by comparing the simulation results of the model glycopeptides to various NMR (3)J coupling constants, NOE distances, and data from molecular dynamics with time-averaged restraints (tar-MD).