Dihedral Angle Distribution Research Articles

Balanced Amino-Acid-Specific Molecular Dynamics Force Field for the Realistic Simulation of Both Folded and Disordered Proteins.

Molecular dynamics (MD) simulations provide a unique atomic-level description of the structure and dynamics of proteins, which is essential for the mechanistic understanding of protein interactions and function in living organisms. However, traditional MD force fields that are optimized for folded proteins often generate overly compact structures and incorrect characteristics of intrinsically disordered proteins (IDPs) and protein regions (IDRs), thereby limiting the quantitative insights that can be gained from MD simulations. We introduce the residue-specific protein force field, ff99SBnmr2, which is derived from ff99SBnmr1 by balancing the backbone dihedral angle potentials in a residue-specific manner to quantitatively reproduce dihedral angle distributions from an experimental coil library. The new force field substantially improves the backbone conformational ensembles of disordered proteins, protein regions, and peptides while keeping well-defined protein structures stable and accurate. This balanced new force field should enable a myriad of applications that require quantitative descriptions of IDPs, IDRs, loop dynamics, and folding/unfolding equilibria in the presence and absence of interaction partners.

Hamiltonian Reweighing To Refine Protein Backbone Dihedral Angle Parameters in the GROMOS Force Field.

Molecular dynamics simulations of proteins depend critically on the underlying force field, which may be parameterized against experimental data or high-quality quantum calculations. Here, we develop search algorithms based on Monte Carlo and steepest descent calculations to optimize the backbone dihedral angle parameters from a single reference simulation. We apply these tools to improve the agreement between simulations of single, capped amino acids and experimentally determined J values and secondary structure propensities of these molecules. The parameters are further refined based on simulations of a set of seven proteins and finally validated in simulations on a large set of 52 protein structures. Improvements in the dihedral angle distributions are observed, and structural propensities of the proteins are reproduced very well. Overall, the GROMOS 54A8_bb parameter set forms an improvement to previous parameter sets, both for small molecules and for protein simulations.

Geometry-based distance for clustering amino acids

ABSTRACTClustering amino acids is one of the most challenging problems in functional and structural prediction of protein. Previous studies have proposed clusters based on measurements of physical and biochemical characteristics of the amino acids such as volume, area, hydrophilicity, polarity, hydrogen bonding, shape, and charge. These characteristics, although important, are less directly related to the protein structure compared to geometrical characteristics such as dihedral angles between amino acids. We propose using the p-value from a test of equality of dihedral-angle distributions as the basis of a distance measure for the clustering. In this novel approach, an energy test is modified to deal with bivariate angular data and the p-value is obtained via a permutation method. The results indicate that the clusters of amino acids have sensible interpretation where Glycine, Proline, and Asparagine each forms a distinct cluster. A simulation study suggests that this approach has good working characteristics to cluster amino acids.

Revealing conformational dynamics of 2′-O-methyl-RNA guanine modified G-quadruplex by replica exchange molecular dynamics

Thrombin-binding DNA aptamer (TBA) can fold into an antiparallel unimolecular G-quadruplex (G4) structure. Different types of modifications lead to various effects on the structure and stability of the G4 structure. Previous study has shown that a modified TBA (mTBA) that 2′-deoxy guanine (dG) at positions 10 and 11 in the TBA sequence were replaced by 2′-O-methyl-RNA guanine (2′OMe-G) can't fold into a well-defined G4 structure. In order to investigate the detailed structural information and probe the instability factors, we successfully employed the replica exchange molecular dynamics (REMD) to characterize the large conformational variations of the mTBA and systemically describe the influences of the 2′OMe-G on the mTBA in terms of conformation variations and the probability distributions of Hoogsteen hydrogen bonds, dihedral, sugar pucker and glycosyl torsion angle. Replacing position 10 with the 2′OMe-G (2′OMe-G10) induced a strong destabilization of the aptamer, while the 2′OMe-G at position 11(2′OMe-G11) was less destabilizing. More importantly, the glycosyl torsion angle and sugar pucker of 2′OMe-G10 were the most critical destabilization factors. These results were in good agreement with the theoretical and experimental results. Moreover, the structure information can be used as guidelines for the further design of modifications on G4 structure.

Glycosylation effects on the structure and dynamics of a full-length Cel7A cellulase

Fungi cellulases are used to degrade cellulose-containing biomass for bioethanol production. Industrial cellulases such as Cel7A from Trichoderma reesei (TrCel7A) are critical in this process. Thus, the understanding of structure and dynamics is crucial for engineering variants with improved cellulolytic activity. This cellulase consists of two domains connected by a flexible and highly glycosylated linker. However, the linker flexibility has hindered the determination of Cel7A complete structure. Herein, based on atomic and sparse data, we applied integrative modelling to build a model of the complete enzyme structure. Next, through simulations, we studied the glycosylation effects on the structure and dynamics of a solubilized TrCel7A. Essential dynamics analysis showed that O-glycosylation in the linker led to the stabilization of protein overall dynamics. O-linked glycans seem to restrict protein dihedral angles distribution in this region, selecting more elongated conformations. Besides the reduced flexibility, functional interdomain motions occurred in a more concerted way in the glycosylated system. In contrast, in the absence of glycosylation, we observed vast conformational plasticity with the functional domains frequently collapsing. We report here evidence that targeting Cel7A linker flexibility by point mutations including modification of glycosylation sites could be a promising design strategy to improve cellulase activity.

Structural and dynamic responses of calcium ion binding loop residues in metallo-proteins

Conformational changes in bio-molecular systems are fundamental to several biological processes. It is important to study changes in responses of underlying microscopic variables, like dihedral angles as conformational change takes place. We perform all-atom simulations and modelling via Langevin equation to illustrate the changes in structural and dynamic responses of dihedral angles of calcium ion binding residues of different proteins in metal ion free (apo) and bound (holo) states. The equilibrium distributions of dihedral angles in apo- and holo-states represent structural response. Our studies show the presence of dihedrals with multiple peaks (isomeric states) separated by barrier heights is more frequent in apo- than in holo-state. The relaxation time-scale of dihedral fluctuations is found to increase linearly with decreasing barrier height due to more frequent barrier re-crossing events. The slow kinetic response of the dihedrals also contributes to slowing down of macro-scale fluctuations, which may be useful to understand kinetics of various bio-molecular processes.

Metal segregation in planetesimals: Constraints from experimentally determined interfacial energies

High temperature experiments have been performed to constrain interfacial energies in a three-phase system (metal–forsterite–silicate melt) representative of partially differentiated planetesimals accreted early in the solar system history, with the aim of providing new insights into the factors affecting the interconnection threshold of metal-rich phases. Experiments were run under controlled oxygen fugacity (ΔNi-NiO=−3) at 1440°C, typically for 24 h. Quantification of the true dihedral angles requires a resolution of at least 30 nm per pixel in order to reveal small-angle wedges of silicate melt at crystal interfaces. At this level of resolution, dihedral angle distributions of silicate melt and olivine appear asymmetric, an observation interpreted in terms of anisotropy of olivine crystals. Based upon the theoretical relation between dihedral angles and interfacial energies in a three-phase system, the relative magnitudes of interfacial energies have been determined to be: γMelt-Ol<γMelt-Ni<γOl-Ni. This order differs from that obtained with experiments using an iron sulfide liquid close to the Fe–FeS eutectic for which γMelt-Sulfide<γMelt-Ol<γOl-Sulfide, implying a lower interconnection threshold for sulfur-rich melts than for pure metallic phases. This dependence of the interconnection threshold on the sulfur content will affect the drainage of metallic phases during melting of small bodies. Assuming a continuous extraction of silicate melt, evolution of the metal volume fraction has been modeled. Several sulfur-rich melts extraction events are possible over a range of temperatures relevant with thermometric data on primitive achondrites (1200–1400°C and 25% of silicate melt extracted). These successive events provide novel insight into the variability of sulfur content in primitive achondrites, which are either representative of a region that experienced sulfide extraction or from a region that accumulated sulfide melt from overlying parts of the parent body.

Amorphous paracrystalline structures from native crystalline cellulose: A molecular dynamics protocol

Cellulose amorphization is a suitable process that allows greater accessibility of cellulolytic enzymes to glycosidic bonds of cellulose, thus improving the yield of bioethanol obtained from lignocellulosic biomass. In a theoretical framework, we demonstrated the amorphization process of two cellulose allomorphs (Iα, Iβ) using a new Molecular Dynamics (MD) protocol at high temperatures. At 700 K, in the high-temperature molten phase, these allomorphs showed the formation of structures with quite amorphous-shell and slightly paracrystalline-core (Am-Par structures) when the degree of polymerization is increased. Applying different characterization methods, we confirmed that Am-Par structures were similar at 700 K, as well as over a temperature ranging from 680 K to 380 K. This confirmation was based on low density of intra-chain hydrogen bonds (HBs), the absence of bands in the region of 3330–3470 cm−1 corresponding to such HBs in the simulated IR, low values of the lateral order index calculated from IR, Q4 and Q6 values close to zero, loss of long-range ordering observed in radial distribution functions, total destruction of crystal unit cell corroborated by X-ray diffraction, and similarity between probability density distribution of dihedral angle ψ with that computed for completely amorphous cellulose. Nonetheless, as revealed by X-ray diffraction results, this protocol seems to provide more crystalline structures starting from cellulose microfibrils having a polymerization degree higher than 10.

Comparison of Forcefields in the Prediction of Intrinsic Residue-Specific Backbone Dihedral Angle Distributions of Blocked Amino Acids

Comparison of Forcefields in the Prediction of Intrinsic Residue-Specific Backbone Dihedral Angle Distributions of Blocked Amino Acids

Experimentally Derived and Computationally Optimized Backbone Conformational Statistics for Blocked Amino Acids.

Experimentally derived, amino acid specific backbone dihedral angle distributions are invaluable for modeling data-driven conformational equilibria of proteins and for enabling quantitative assessments of the accuracies of molecular mechanics force fields. The protein coil library that is extracted from analysis of high-resolution structures of proteins has served as a useful proxy for quantifying intrinsic and context-dependent conformational distributions of amino acids. However, data that go into coil libraries will have hidden biases, and ad hoc procedures must be used to remove these biases. Here, we combine high-resolution biased information from protein structural databases with unbiased low-resolution information from spectroscopic measurements of blocked amino acids to obtain experimentally derived and computationally optimized coil-library landscapes for each of the 20 naturally occurring amino acids. Quantitative descriptions of conformational distributions require parsing of data into conformational basins with defined envelopes, centers, and statistical weights. We develop and deploy a numerical method to extract conformational basins. The weights of conformational basins are optimized to reproduce quantitative inferences drawn from spectroscopic experiments for blocked amino acids. The optimized distributions serve as touchstones for assessments of intrinsic conformational preferences and for quantitative comparisons of molecular mechanics force fields.

Applying cold sintering process to a proton electrolyte material: CsH2PO4

The Cold Sintering Process (CSP) was applied to CsH2PO4, a proton conducting electrolyte. The powders were sintered between 120 °C and 200 °C under 300 MPa for 1 h and the ceramics investigated for their respective structure-property-process relations. The microstructure development of the CsH2PO4 materials was characterized for grain size, and dihedral angle distributions for a variety of the CSP processing conditions. The electrical properties of the cold sintered CsH2PO4 were characterized through electrochemical impedance spectroscopy over a temperature range between 120 °C and 200 °C. The data suggests that the proton conductivity is 2.30 × 10−4 Scm-1 at 200 °C with good repeatability during cycled measurements.

Molecular dynamics study of deformation mechanisms of poly(vinyl alcohol) hydrogel

ABSTRACTMolecular dynamics (MD) simulations have been performed on the physically crosslinking poly(vinyl alcohol) (PVA) hydrogel to study the deformation mechanisms under uniaxial tensile conditions. The distributions of hydroxyl oxygens and dihedral angle and the number of hydrogen bonds have been analysed to study the structure of the hydrogel. The water content and temperature dependency of mechanical properties have been investigated. The energy contributions from the partially united atom potential have been calculated as a function of strain. It is found that the stress–strain curve comprises toe region, linear region and yield and failure region which is close to most biomaterials. In the toe and yield region, all the contributions to the internal energy change a little. However, in the linear region, the bond stretching and angle bending energy increase rapidly and mainly dominate the region, and the energy increases more rapidly with the increasing water content but the decreasing temperature. The degree of crosslinking decreases with the increasing deformation. The polymer chains occur significant torsional activity in the toe region. Hydrogen bonds are stable in the toe and yield region, but the hydrogen bonds between hydroxyl groups and waters decrease in the linear region.

Geometric symmetry modulated spin polarization of electron transport in graphene-like zigzag FeB2 nanoribbons

Due to electron deficiency, the graphene-like honeycomb structure of boron is unstable. By introducing Fe atoms, it is reported that FeB2 monolayer has excellent dynamic and thermal stabilities at room temperature. Based on first-principles calculations, the spin-dependent transport of zigzag FeB2 nanoribbons (ZFeB2NRs) under ferromagnetic state (FM) is investigated. It is found that, around the Fermi level, FeB-terminated (or FeFe-terminated) ZFeB2NRs exhibit completely spin-polarized (or spin-unpolarized) transmission, and BB-terminated configurations exhibit completely unpolarized or partially polarized transmission. Further analysis shows that, the hinge dihedral angle has a switching effect on the transport channels, and the spin polarization of the transmission is determined by the symmetry of the distribution of hinge dihedral angles along the transverse direction of the ribbon, where symmetric/asymmetric distribution induces spin-unpolarized/polarized transmission. Moreover, such a symmetry effect is found to be robust to the width of the ribbon, showing great application potential. Our findings may throw light on the development of B-based spintronic devices.

Molecular Design and Property Prediction of Sterically Confined Polyimides for Thermally Stable and Transparent Materials.

To meet the demand for next-generation flexible optoelectronic devices, it is crucial to accurately establish the chemical structure-property relationships of new optical polymer films from a theoretical point of view, prior to production. In the current study, computer-aided simulations of newly designed poly(ester imide)s (PEsIs) with various side groups (–H, –CH3, and –CF3) and substituted positions were employed to study substituent-derived steric effects on their optical and thermal properties. From calculations of the dihedral angle distribution of the model compounds, it was found that the torsion angle of the C–N imide bonds was effectively constrained by the judicious introduction of di-, tetra-, and hexa-substituted aromatic diamines with –CF3 groups. A high degree of fluorination of the PEsI repeating units resulted in weaker intra- and intermolecular conjugations. Their behavior was consistent with the molecular orbital energies obtained using density functional theory (DFT). In addition, various potential energy components of the PEsIs were investigated, and their role in glass-transition behavior was studied. The van der Waals energy (EvdW) played a crucial role in the segmental chain motion, which had an abrupt change near glass-transition temperature (Tg). The more effective steric effect caused by –CF3 substituents at the 3-position of the 4-aminophenyl group significantly improved the chain rigidity, and showed high thermal stability (Tg > 731 K) when compared with the –CH3 substituent at the same position, by highly distorting (89.7°) the conformation of the main chain.

Study on mechanical properties of polyethylene with chain branching in atomic scale by molecular dynamics simulation

The effects of length and content of chain branching on the mechanical properties of polyethylene (PE) in atomic scale were examined by molecular dynamics (MD) simulations. Methyl-, ethyl- and butyl-groups were adopted as branched chains to distribute along PE backbones. Plastic flow deformation was captured by providing a uniaxial tensile loading at a given strain rate, which shows the characteristic of rate dependence. Current results are in reasonable agreements with existing experimental data. The statistical results show that the longer length of chain branching induces lower equilibrium density and higher yield strength of branched PE. In addition, higher content of chain branching brings higher equilibrium density and lower yield strength of branched PE. It is assumed that the distribution of dihedral angles influences the deformation of PE definitely. The non-bond interactions contribute to the load-bearing capacity of PE largely. Branched PE shows big differences on mechanical behaviours comparing with the linear one. Chain branching distribution also greatly affects the performance of PE, which needs a further discussion.

Impact of a non-synonymous Q281R polymorphism on structure of human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2 ).

Non-synonymous single nucleotide polymorphisms (nsSNPs) are genetic variations at single base resulting in an amino acid change which have been associated with various complex human diseases. The human Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) gene harbours a rare Q281R polymorphism which was previously reported to cause loss of enzymatic function. Lp-PLA2 is an important enzyme which catalyzes the hydrolysis of polar phospholipids releasing pro-atherogenic and pro-inflammatory mediators involved in the pathogenesis of atherosclerosis. Our current study is aimed at elucidating the structural and functional consequences of Q281R polymorphism on Lp-PLA2 . The Q281R mutation is classified as deleterious and causes protein instability as deduced from evolutionary, folding free energy changes and Support vector machine (SVM)-based methods. A Q281R mutant structure was deciphered using homology modelling approach and was validated using phi and psi dihedral angles distribution, ERRAT, Verify_3D scores, Protein Structure Analysis (ProSA) energ,y and Z-score. A decreased hydrophobic interactions and weaker substrate binding affinity was observed in the mutant compared to the wild- type (WT) using molecular docking. Further, the mutant displayed enhanced structural flexibility particularly in the low density lipoprotein (LDL) binding domain, decreased solvent accessibility of catalytic residues-Phe274 and Ser273 and increased Cɑ distance between Phe274 and Leu153 and large conformational entropy change as inferred from all-atom molecular dynamics (MD) simulation and essential dynamics (ED) studies. Our results corroborate well with previous experimental studies and thus these aberrations in the Q281R mutant structure may help explain the molecular basis of loss of enzyme activity.

Lipid Configurations from Molecular Dynamics Simulations

The extent to which current force fields faithfully reproduce conformational properties of lipids in bilayer membranes, and whether these reflect the structural principles established for phospholipids in bilayer crystals, are central to biomembrane simulations. We determine the distribution of dihedral angles in palmitoyl-oleoyl phosphatidylcholine from molecular dynamics simulations of hydrated fluid bilayer membranes. We compare results from the widely used lipid force field of Berger et al. with those from the most recent C36 release of the CHARMM force field for lipids. Only the CHARMM force field produces the chain inequivalence with sn-1 as leading chain that is characteristic of glycerolipid packing in fluid bilayers. The exposure and high partial charge of the backbone carbonyls in Berger lipids leads to artifactual binding of Na+ ions reported in the literature. Both force fields predict coupled, near-symmetrical distributions of headgroup dihedral angles, which is compatible with models of interconverting mirror-image conformations used originally to interpret NMR order parameters. The Berger force field produces rotamer populations that correspond to the headgroup conformation found in a phosphatidylcholine lipid bilayer crystal, whereas CHARMM36 rotamer populations are closer to the more relaxed crystal conformations of phosphatidylethanolamine and glycerophosphocholine. CHARMM36 alone predicts the correct relative signs of the time-average headgroup order parameters, and reasonably reproduces the full range of NMR data from the phosphate diester to the choline methyls. There is strong motivation to seek further experimental criteria for verifying predicted conformational distributions in the choline headgroup, including the 31P chemical shift anisotropy and 14N and CD3 NMR quadrupole splittings.

New Knowledge-Based Scoring Function with Inclusion of Backbone Conformational Entropies from Protein Structures.

Accurate prediction of a protein's structure requires a reliable free energy function that consists of both enthalpic and entropic contributions. Although considerable progresses have been made in the calculation of potential energies in protein structure prediction, the computation for entropies of protein has lagged far behind, due to the challenge that estimation of entropies often requires expensive conformational sampling. In this study, we have used a knowledge-based approach to estimate the backbone conformational entropies from experimentally determined structures. Instead of conducting computationally expensive MD/MC simulations, we obtained the entropies of protein structures based on the normalized probability distributions of back dihedral angles observed in the native structures. Our new knowledge-based scoring function with inclusion of the backbone entropies, which is referred to as ITScoreDA or ITDA, was extensively evaluated on 16 commonly used decoy sets and compared with 50 other published scoring functions. It was shown that ITDA is significantly superior to the other tested scoring functions in selecting native structures from decoys. The present study suggests the role of backbone conformational entropies in protein structures and provides a way for fast estimation of the entropic effect.

Three-dimensional study by synchrotron radiation computed tomography of melt distribution in samples doped to enhance contrast

AbstractThe three-dimensional distribution of melt in partially molten synthetic samples compositionally corresponding to diopside (90 wt.%)–anorthite (10 wt.%) and doped with PbO, WO3, MoO3, or Cs2O to enhance contrast was studied by X-ray computed tomography (CT) with synchrotron radiation. The heavy elements were strongly concentrated in the melt and contributed to an increase of the X-ray linear attenuation coefficient (LAC) of it. PbO was found to be compatible with silicate melt (&gt;20 wt.% in solution) and incompatible with diopside crystals. Other oxides WO3 (∼10 wt.%), MoO3 (∼5 wt.%) and Cs2O (&lt; 5 wt.%) are also soluble only in the melt. Such doping is useful not only for LAC control in X-ray CT measurements, but also for systematic control of the structure (wetting properties, distribution and connectivity) of partial melt. This technique gives basic information for discussion of the 3D distribution of partial melt having different wetting properties. As PbO was most effective in visualization of the diopside–anorthite partially molten system, CT images of the PbO-bearing sample were used for further 3D investigation of distribution. A distribution of dihedral angles at solid-melt-solid triple junctions ranging from 22 to 55° was observed with the 3D data. This range in angle distribution was probably caused by anisotropy of crystals and the result supports the argument that there is some limitation in a theoretical framework of stereology which estimates the 3D structure based on 2D observations. Investigators have begun to apply X-ray CT to the study of the 3D distribution of partial melts in rocks using synchrotron radiation. Our study on the effect of doping is one approach for developing a technique to investigate 3D melt distribution.

MD study of structure and dynamic properties of the 1-n-alkyl-3-methylimidazolium tris(perfluoroalkyl)trifluorophosphate ionic liquids

In this study, we applied classical molecular dynamics (MD) simulations to understand the structure, dynamics and transport properties of the room-temperature 1-alkyl-3-methylimidazolium family with tris(perfluoroalkyl)trifluorophosphate ionic liquids, abbreviated as [Cnmim][eFAP]. Calculated densities of ionic liquids agree well with experimental data. Local structures were characterized by studying the center-of-mass (COM) and partial site-site RDFs, combined distribution functions (CDFs) and dihedral angles distribution of n-alkyl side chains in the imidazolium cations. The hydrogen bonding between Fluor atoms of anions and hydrogen atoms of imidazolium ring of cations were studied by contour maps of CDFs. Also, dynamical properties of these ILs such as mean-square displacement (MSDs) for center-of-mass of ions, ionic diffusion coefficients and the cationic transference numbers are calculated by simulation in the NVT ensemble. Results show that the length of alkyl-side chain of cation is the major factor to affect these properties.