Using one‐step perturbation to predict the effect of changing force‐field parameters on the simulated folding equilibrium of a β‐peptide in solution

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force‐field parameters. Here, we use the one‐step perturbation technique to predict the change of the free enthalpy of folding of a β‐peptide in methanol solution due to changing a variety of force‐field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut‐off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction‐field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom‐positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one‐step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one‐step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force‐field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Coarse‐Grained Simulations of Model Polymer Nanofibres

We describe the development of a coarse‐grained (CG) force field for nylon‐6 (polycaprolactam) and its application to the simulation of the structure and macromolecular dynamics within cylindrical fibres formed by this polymer, having diameters in the 14–28 nm range. Our CG model is based on the MARTINI force field for the non‐bonded interactions and on Boltzmann‐inverted gas‐phase atomistic simulations for intramolecular stretching and bending energies. The simulations are carried out on infinite, isolated nanofibres at temperatures of 300, 400 and 500 K, with different starting configurations. Starting from ordered chain‐extended configurations, we simulate the melting of the polymer in the nanofibres and, after cooling back to room temperature, its re‐crystallization in a chain‐folded lamellar configuration. This agrees with experimental observations on electrospun nylon‐6 nanofibres and demonstrated the suitability of the approach for the simulation of these systems. The effect of nanoscale confinement on the structure and dynamics of the polymer chains is extensively discussed.

     

Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P,PM3‐CARB1/TIP3P,and SCC‐DFTB‐D/TIP3P predictions with experiment

The 3D‐structure of extracellular matrix glycosaminoglycans is central to function, but is currently poorly understood. Resolving this will provide insight into their heterogeneous biological roles and help to realize their significant therapeutic potential. Glycosaminoglycan chemical isoforms are too numerous to study experimentally and simulation provides a tractable alternative. However, best practice for accurate calculation of glycosaminoglycan 3D‐structure within biologically relevant nanosecond timescales is uncertain. Here, we evaluate the ability of three potentials to reproduce experimentally observed glycosaminoglycan monosaccharide puckering, disaccharide 3D‐conformation, and characteristic solvent interactions. Temporal dynamics of unsulfated chondroitin, chondroitin‐4‐sulfate, and hyaluronan β(1→3) disaccharides were simulated within TIP3P explicit solvent unrestrained for 20 ns using the GLYCAM06 force‐field and two semi‐empirical quantum mechanics methods, PM3‐CARB1 and SCC‐DFTB‐D (both within a hybrid QM/MM formalism). Comparison of calculated and experimental properties (vicinal couplings, nuclear Overhauser enhancements, and glycosidic linkage geometries) showed that the carbohydrate‐specific parameterization of PM3‐CARB1 imparted quantifiable benefits on monosaccharide puckering and that the SCC‐DFTB‐D method (including an empirical correction for dispersion) best modeled the effects of hexosamine 4‐sulfation. However, paradoxically, the most approximate approach (GLYCAM06/TIP3P) was the best at predicting monosaccharide puckering, 3D‐conformation, and solvent interactions. Our data contribute to the debate and emerging consensus on the relative performance of these levels of theory for biological molecules. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

The SAAP force field: Development of the single amino acid potentials for 20 proteinogenic amino acids and Monte Carlo molecular simulation for short peptides

Molecular simulation by using force field parameters has been widely applied in the fields of peptide and protein research for various purposes. We recently proposed a new all‐atom protein force field, called the SAAP force field, which utilizes single amino acid potentials (SAAPs) as the fundamental elements. In this article, whole sets of the SAAP force field parameters in vacuo, in ether, and in water have been developed by ab initio calculation for all 20 proteinogenic amino acids and applied to Monte Carlo molecular simulation for two short peptides. The side‐chain separation approximation method was employed to obtain the SAAP parameters for the amino acids with a long side chain. Monte Carlo simulation for Met‐enkephalin (CHO‐Tyr‐Gly‐Gly‐Phe‐Met‐NH₂) by using the SAAP force field revealed that the conformation in vacuo is mainly controlled by strong electrostatic interactions between the amino acid residues, while the SAAPs and the interamino acid Lennard‐Jones potentials are predominant in water. In ether, the conformation would be determined by the combination of the three components. On the other hand, the SAAP simulation for chignolin (H‐Gly‐Tyr‐Asp‐Pro‐Glu‐Thr‐Gly‐Thr‐Trp‐Gly‐OH) reasonably reproduced a native‐like β‐hairpin structure in water although the C‐terminal and side‐chain conformations were different from the native ones. It was suggested that the SAAP force field is a useful tool for analyzing conformations of polypeptides in terms of intrinsic conformational propensities of the single amino acid units. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

CHARMM36 all‐atom additive protein force field: Validation based on comparison to NMR data

Protein structure and dynamics can be characterized on the atomistic level with both nuclear magnetic resonance (NMR) experiments and molecular dynamics (MD) simulations. Here, we quantify the ability of the recently presented CHARMM36 (C36) force field (FF) to reproduce various NMR observables using MD simulations. The studied NMR properties include backbone scalar couplings across hydrogen bonds, residual dipolar couplings (RDCs) and relaxation order parameter, as well as scalar couplings, RDCs, and order parameters for side‐chain amino‐ and methyl‐containing groups. It is shown that the C36 FF leads to better correlation with experimental data compared to the CHARMM22/CMAP FF and suggest using C36 in protein simulations. Although both CHARMM FFs contains the same nonbond parameters, our results show how the changes in the internal parameters associated with the peptide backbone via CMAP and the χ₁ and χ₂ dihedral parameters leads to improved treatment of the analyzed nonbond interactions. This highlights the importance of proper treatment of the internal covalent components in modeling nonbond interactions with molecular mechanics FFs. © 2013 Wiley Periodicals, Inc.     

Hydrogen‐bonding interactions in the active site of a low molecular weight protein‐tyrosine phosphatase

Molecular dynamics simulation of the Michaelis complex, phospho‐enzyme intermediate, and the wild‐type and C12S mutant have been carried out to examine hydrogen‐bonding interactions in the active site of the bovine low molecular weight protein‐tyrosine phosphatase (BPTP). It was found that the S_γ atom of the nucleophilic residue Cys‐12 is ideally located at a position opposite from the phenylphosphate dianion for an inline nucleophilic substitution reaction. In addition, electrostatic and hydrogen‐bonding interactions from the backbone amide groups of the phosphate‐binding loop strongly stabilize the thiolate anion, making Cys‐12 ionized in the active site. In the phospho‐enzyme intermediate, three water molecules are found to form strong hydrogen bonds with the phosphate group. In addition, another water molecule can be identified to form bridging hydrogen bonds between the phosphate group and Asp‐129, which may act as the nucleophile in the subsequent phosphate hydrolysis reaction, with Asp‐129 serving as a general base. The structural difference at the active site between the wild‐type and C12S mutant has been examined. It was found that the alkoxide anion is significantly shifted toward one side of the phosphate binding loop, away from the optimal position enjoyed by the thiolate anion of the wild‐type enzyme in an S_N2 process. This, coupled with the high pK_a value of an alcoholic residue, makes the C12S mutant catalytically inactive. These molecular dynamics simulations provided details of hydrogen bonding interactions in the active site of BPTP, and a structural basis for further studies using combined quantum mechanical and molecular mechanical potential to model the entire dephosphorylation reaction by BPTP. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1192–1203, 2000     

Synthesis and characterization of a novel long‐alkyl‐chain ester‐substituted benzimidazole gelator and its octan‐1‐ol solvate

The synthesis of a novel benzimidazole derivative with a long‐chain‐ester substituent, namely methyl 8‐[4‐(1H‐benzimidazol‐2‐yl)phenoxy]octanoate, (3), is reported. Ester (3) shows evidence of aggregation in solution and weak gelation ability with toluene. The octan‐1‐ol solvate, methyl 8‐[4‐(1H‐benzimidazol‐2‐yl)phenoxy]octanoate octan‐1‐ol monosolvate, C₂₂H₂₆N₂O₃·C₈H₁₈O, (4), exhibits a four‐molecule hydrogen‐bonded motif in the solid state, with N—H…O hydrogen bonds between benzimidazole molecules and O—H…N hydrogen bonds between the octan‐1‐ol solvent molecules and the benzimidazole unit. The alkyl chains of the ester and the octan‐1‐ol molecules are in unfolded conformations. The phenylene ring is canted by 10.27 (6)° from the plane of the benzimidazole ring system. H…C contacts make up 20.7% of the Hirshfeld surface coverage. Weak C—H…π interactions involving the benzimidazole alkyl chain and three aromatic rings are observed.     

Supramolecular Hydrogels Based on L‐Phenylalanine Derivatives with a Positively Charged Terminal Group

A new hydrogelator based on L ‐phenylalanine with a long hydrophobic chain and positively charged terminus was synthesized, and its gelation behavior in H₂O was investigated. Polarized optical microscopy (POM), field emission scanning electron microscopy (FE‐SEM), and X‐ray diffraction (XRD) results indicate that the hydrogelator self‐assembles into fibres‐like aggregates which then lead to the formation of a hydrogel. ¹H‐NMR and CD spectra of hydrogels and aqueous solution revealed that intermolecular H‐bonding between the amide groups was the driving force for gelation. A luminescence study, in which ANS (8‐anilinonaphthalene‐1‐sulfonic acid) was used as a probe, indicated that the hydrophobic interactions between long chains were the driving force for gelation. Consequently, it was proved that the hydrogelator self‐assembles into fibre‐like aggregates and then forms supramolecular hydrogels through the H‐bonding and hydrophobic interactions.     

N‐{4‐Bromo‐2‐[(3‐bromo‐1‐phenylsulfonyl‐1H‐indol‐2‐yl)methyl]‐5‐methoxyphenyl}acetamide

In the title compound, C₂₄H₂₀Br₂N₂O₄S, the indole ring system is planar and the S atom has a distorted tetrahedral configuration. The sulfonyl‐bound phenyl ring is orthogonal to the indole ring system and the conformation of the phenyl­sulfonyl substituent with respect to the indole moiety is influenced by intramolecular C—H⃛O hydrogen bonds involving the two sulfonyl O atoms. The mean plane through the acetyl­amido group makes a dihedral angle of 57.0 (1)° with the phenyl ring of the benzyl moiety. In the crystal, glide‐related mol­ecules are linked together by N—H⃛O hydrogen bonds and C—H⃛π interactions to form molecular chains, which extend through the crystal. Inversion‐related chains are interlinked by C—H⃛π interactions to form molecular layers parallel to the bc plane. These layers are interconnected through π–π interactions involving the five‐ and six‐membered rings of the indole moiety.     

柔性金属—有机骨架材料中已烷的扩散研究

本工作将MM3力场进行了扩展,使其可用于描述其它IRMOF材料的柔韧性;在此基础上,我们采用分子动力学模拟研究了柔性IRMOF-1和-16材料中已烷的扩散。 本文重点研究了温度和分子数对己烷自扩散系数、扩散机理,以及骨架柔性的影响。结果表明,分子数是影响扩散路径的重要因素。其次,IRMOF-16的柔性强于IRMOF-1。 工作的结论有助于进一步研究链状分子在柔性MOF材料中的扩散。     

Improved treatment of cyclic β‐amino acids and successful prediction of β‐peptide secondary structure using a modified force field: AMBER*C

We added parameters to the AMBER* force field to model cyclic β‐amino acid derivatives more accurately within the commonly used MacroModel program. In an effort to generate an improved treatment of cyclohexane and cyclopentane conformational preferences, carbon–carbon torsional parameters were modified and incorporated into a force field we call AMBER*C. Simulation of trans‐2‐aminocyclohexanecarboxylic acid (trans‐ACHC) and trans‐2‐aminocyclopentanecarboxylic acid (trans‐ACPC) derivatives using AMBER*C produces more realistic energy differences between (pseudo)diaxial and (pseudo)diequatorial conformations than does simulation using AMBER*. AMBER*C molecular dynamics simulations more accurately reproduce the experimental hydrogen‐bonding tendencies of simple diamide derivatives of trans‐ACHC and trans‐ACPC than do simulations using the AMBER* force field. More importantly, this modified force field allows accurate qualitative prediction of the helical secondary structures adopted by β‐amino acid homo‐oligomers. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 763–773, 2000     

Self‐inclusion in 5,11,17,23‐tetra‐tert‐butyl‐26,27,28‐tri­hydroxy­‐25‐(methoxy­carbonyl­methoxy)calix­[4]­arene chloro­form trisolvate

The title compound, C₄₇H₆₀O₆·3CHCl₃, is the first example of a lower‐rim mono‐ester calixarene derivative to be crystallographically characterized. The cone conformation adopted by the macrocycle is stabilized by three intramolecular hydrogen bonds. Self‐inclusion of the methyl ester chain in the cavity of an adjacent mol­ecule gives rise to infinite chains parallel to the c axis. C—H⋯π interactions involving the methyl group most imbedded in the cavity contribute to the stabilization of the system.     

[2,5‐Bis(2,2′‐bipyridyl‐6‐yl)‐3,4‐diazahexa‐2,4‐diene]dichloridomanganese(II): from a mononuclear compound to a three‐dimensional supramolecular framework through C—H...Cl hydrogen bonds and π–π stacking interactions

The title compound, [MnCl₂(C₂₄H₂₀N₆)], has been synthesized and characterized based on the multifunctional ligand 2,5‐bis(2,2′‐bipyridyl‐6‐yl)‐3,4‐diazahexa‐2,4‐diene (L). The Mn^II centre is five‐coordinate with an approximately square‐pyramidal geometry. The L ligand acts as a tridendate chelating ligand. The mononuclear molecules are bridged into a one‐dimensional chain by two C—H...Cl hydrogen bonds. These chains are assembled into a two‐dimensional layer through π–π stacking interactions between adjacent uncoordinated bipyridyl groups. Furthermore, a three‐dimensional supramolecular framework is attained through π–π stacking interactions between adjacent coordinated bipyridyl groups.     

Supramolecular assembly of H‐bonded side‐chain polymers containing conjugated pyridyl H‐acceptor pendants and various low‐band‐gap H‐donor dyes bearing cyanoacrylic acid groups for organic solar cell applications

Novel supramolecular side‐chain polymers were constructed by complexation of proton acceptor (H‐acceptor) polymers, i.e., side‐chain conjugated polymers P1–P2 containing pyridyl pendants, with low‐band‐gap proton donor (H‐donor) dyes S1–S4 (bearing terminal cyanoacrylic acids) in a proper molar ratio. Besides unique mesomorphic properties confirmed by DSC and XRD results, the H‐bonds of supramolecular side‐chain structures formed by pyridyl H‐acceptors and cyanoacrylic acid H‐donors were also confirmed by FTIR measurements. H‐donor dyes S1–S4 in solid films exhibited broad absorption peaks located in the range of 471–490 nm with optical band‐gaps of 1.99–2.14 eV. Furthermore, H‐bonded polymer complexes P1/S1–P1/S4 and P2/S1–P2/S4 exhibited broad absorption peaks in the range of 440–462 nm with optical band‐gaps of 2.11–2.25 eV. Under 100 mW/cm² of AM 1.5 white‐light illumination, the bulk heterojunction polymer solar cell (PSC) devices containing an active layer of H‐bonded polymer complexes P1/S1–P1/S4 and P2/S1–P2/S4 (as electron donors) mixed with [6,6]‐phenyl C₆₁ butyric acid methyl ester (i.e., PCBM, as an electron acceptor) in the weight ratio of 1:1 were investigated. The PSC device containing H‐bonded polymer complex P1/S3 mixed with PCBM (1:1 w/w) gave the best preliminary result with an overall power conversion efficiency (PCE) of 0.50%, a short‐circuit current of 3.17 mA/cm², an open‐circuit voltage of 0.47 V, and a fill factor of 34%. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5998–6013, 2009     

Monomolecular sheets of propeller‐shaped triethyl 4,4′,4′′‐[benzene‐1,3,5‐triyltris(ethyne‐2,1‐diyl)]tribenzoate deuterochloroform monosolvate

The title compound, C₃₉H₃₀O₆·CDCl₃, has a chemical threefold axis and an approximately planar structure, with an ethoxycarbonyl substituent on each of the terminal benzenes oriented in the same direction, thus forming a propeller‐shaped molecule. This molecule is of particular interest in the field of metal–organic frameworks (MOFs), where its hydrolyzed analogue forms MOF structures with high surface areas. The benzene ring which occupies the centre of the molecule forms π–π interactions to the equivalent benzene ring at a perpendicular distance of 3.32 (1) Å. Centrosymmetric dimers formed in this way are interconnected by intermolecular C—H...π interactions with a rather short H...CgA distance of 2.51 Å (CgA is the centroid of the central benzene ring). The molecules are arranged in regular parallel sheets. Within a sheet, molecules are interconnected via C—H...O interactions where all carbonyl O atoms participate in weak hydrogen bonds as hydrogen‐bond acceptors. Neighbouring sheets are connected through the above‐mentioned π–π and C—H...π interactions.     

An Easy Access to Organic Salt‐Based Stimuli‐Responsive and Multifunctional Supramolecular Hydrogels

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its β‐alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table‐top rheology and dynamic rheology. FTIR, variable‐temperature ¹H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π–π stacking in hydrogelation. Single‐crystal X‐ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide–amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli‐responsive and were capable of sensing ammonia and adsorbing water‐soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.     

mer‐Bis(1,4‐dibenzoylthiosemicarbazidato‐κ3O,N,O′)cobalt(II)

The title complex, [Co(C₁₅H₁₂N₃O₂S)₂], consists of an octahedrally coordinated Co^II ion, with two crystallographically independent 1,4‐dibenzoylthiosemicarbazidate ligands in a tridentate mer coordination [Co—O = 2.064 (3)–2.132 (3) Å and Co—N = 2.037 (3)–2.043 (3) Å]. There are intermolecular N—H...S hydrogen bonds involving one ligand and strong π–π stacking interactions involving the other ligand, resulting in a three‐dimensional supramolecular framework. The hydrogen bonds and π–π interactions, as well as different intramolecular aryl–benzamide H—C...H(—N) distances, give rise to a difference in conformation between the two ligands.     

Two seven‐membered heterocycles with 1,2‐diaza ring N atoms: 3,5,7‐triphenyl‐1,2‐diazacyclohepta‐1(7),2‐diene and 3,7‐bis(2‐hydroxyphenyl)‐5‐phenyl‐1,2‐diazacyclohepta‐1(7),2‐diene

The title compounds, 3,5,7‐triphenyl‐1,2‐diazacyclohepta‐1(7),2‐diene, C₂₃H₂₀N₂, (I), and 3,7‐bis(2‐hydroxyphenyl)‐5‐phenyl‐1,2‐diazacyclohepta‐1(7),2‐diene, C₂₃H₂₀N₂O₂, (II), constitute the first structurally characterized examples of seven‐membered heterocycles with 1,2‐diaza ring N atoms. Compound (I) crystallizes in the space group P, with two independent molecules in the asymmetric unit that differ in the conformation of one of the phenyl rings, while (II) crystallizes in the space group C2/c. The C₅N₂ ring in each of (I) and (II) adopts a twist‐boat conformation. Compound (I) exhibits neither C—H...π interactions nor π–π stacking interactions, whereas (II) shows both intramolecular O—H...N hydrogen bonds and a C—H...π interaction that joins the molecules into an infinite chain in the [010] direction.     

Van Der Waals heterogeneous layer‐layer carbon nanostructures involving π···H‐C‐C‐H···π···H‐C‐C‐H stacking based on graphene and graphane sheets

Noncovalent interactions involving aromatic rings, such as π···π stacking, CH···π are very essential for supramolecular carbon nanostructures. Graphite is a typical homogenous carbon matter based on π···π stacking of graphene sheets. Even in systems not involving aromatic groups, the stability of diamondoid dimer and layer‐layer graphane dimer originates from C − H···H − C noncovalent interaction. In this article, the structures and properties of novel heterogeneous layer‐layer carbon‐nanostructures involving π···H‐C‐C‐H···π···H‐C‐C‐H stacking based on [n ]‐graphane and [n ]‐graphene and their derivatives are theoretically investigated for n = 16–54 using dispersion corrected density functional theory B3LYP‐D3 method. Energy decomposition analysis shows that dispersion interaction is the most important for the stabilization of both double‐ and multi‐layer‐layer [n ]‐graphane@graphene. Binding energy between graphane and graphene sheets shows that there is a distinct additive nature of CH···π interaction. For comparison and simplicity, the concept of H‐H bond energy equivalent number of carbon atoms (noted as NHEQ), is used to describe the strength of these noncovalent interactions. The NHEQ of the graphene dimers, graphane dimers, and double‐layered graphane@graphene are 103, 143, and 110, indicating that the strength of C‐H···π interaction is close to that of π···π and much stronger than that of C‐H···H‐C in large size systems. Additionally, frontier molecular orbital, electron density difference and visualized noncovalent interaction regions are discussed for deeply understanding the nature of the C‐H···π stacking interaction in construction of heterogeneous layer‐layer graphane@graphene structures. We hope that the present study would be helpful for creations of new functional supramolecular materials based on graphane and graphene carbon nano‐structures. © 2017 Wiley Periodicals, Inc.