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1.  Performance of Møller-Plesset second-order perturbation theory and density functional theory in predicting the interaction between stannylenes and aromatic molecules 
The performances of Møller-Plesset second-order perturbation theory (MP2) and density functional theory (DFT) have been assessed for the purposes of investigating the interaction between stannylenes and aromatic molecules. The complexes between SnX2 (where X = H, F, Cl, Br, and I) and benzene or pyridine are considered. Structural and energetic properties of such complexes are calculated using six MP2-type and 14 DFT methods. The assessment of the above-mentioned methods is based on the comparison of the structures and interaction energies predicted by these methods with reference computational data. A very detailed analysis of the performances of the MP2-type and DFT methods is carried out for two complexes, namely SnH2-benzene and SnH2-pyridine. Of the MP2-type methods, the reference structure of SnH2-benzene is reproduced best by SOS-MP2, whereas SCS-MP2 is capable of mimicking the reference structure of SnH2-pyridine with the greatest accuracy. The latter method performs best in predicting the interaction energy between SnH2 and benzene or pyridine. Among the DFT methods, ωB97X provides the structures and interaction energies of the SnH2-benzene and SnH2-pyridine complexes with good accuracy. However, this density functional is not as effective in reproducing the reference data for the two complexes as the best performing MP2-type methods. Next, the DFT methods are evaluated using the full test set of SnX2-benzene and SnX2-pyridine complexes. It is found that the range-separated hybrid or dispersion-corrected density functionals should be used for describing the interaction in such complexes with reasonable accuracy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-015-2589-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4326664  PMID: 25677452
Benchmarking; MP2; DFT; Benzene; Pyridine; Stannylene
2.  s-Block metallabenzene: aromaticity and hydrogen adsorption 
Second group metal dimers can replace the carbon atom in benzene to form metallabenzene (C5H6M2) compounds. These complexes possess some aromatic character and promising hydrogen adsorption properties. In this study, we investigated the aromatic character of these compounds using aromaticity indices and molecular orbital analysis. To determine the nature of interactions between hydrogen and the metallic center, variation-perturbational decomposition of interaction energy was applied together with ETS-NOCV analysis. The results obtained suggest that the aromatic character comes from three π orbitals located mainly on the C5H5− fragment. The high hydrogen adsorption energy (up to 6.5 kcal mol−1) results from two types of interaction. In C5H6Be2, adsorption is controlled by interactions between the empty metal orbital and the σ orbital of the hydrogen molecule (Kubas interaction) together with corresponding back-donation interactions. Other C5H6M2 compounds adsorb H2 due to Kubas interactions enhanced by H2–π interactions.
Graphical AbstractFirst π orbital in C5H6Be2
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2552-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4309903  PMID: 25631918
Metallabenzene; Metallaromaticity; Kubas interactions; Hydrogen adsorption; Hydrogen storage
3.  Hydrogen bridges of polycyclic aromatic systems with O-H···O bonds — a gas-phase vs. solid-state Car-Parrinello study 
The current study belongs to a series of investigations of polycyclic aromatic compounds containing intramolecular hydrogen bonds. Close proximity of the coupled aromatic system and hydrogen bridges gives rise to resonance-assisted hydrogen bonding phenomena. Substituted naphthols are ideally suited for this kind of investigation. The parent compound, 1-hydroxy-8-methoxy-3-methylnaphthalene, and its derivative, 1-bromo-5-hydroxy-4-isopropoxy-7-methylnaphthalene, both with known crystal structure, are investigated. Car-Parrinello molecular dynamics (CPMD) is chosen as a theoretical background for this study. Gas phase and solid state simulations are carried out. The effect of Grimme’s dispersion corrections is also included. The report presents time evolution of structural parameters, spectroscopic signatures based on the CPMD simulations, and comparison with available experimental data. We show that the proton transfer phenomena do not occur within the simulations, which is consistent with evaluation based on the acidity of the donor and acceptor sites. The effects of the substitution in the aromatic system and change of the environment (gas vs. condensed phase) are of similar magnitude.
PMCID: PMC4305098  PMID: 25617206
Car-Parrinello molecular dynamics; Intramolecular O-H···O hydrogen bond; Naphthol derivatives; Vibrational features
4.  [No title available] 
PMCID: PMC4295769  PMID: 24898939
5.  Computational studies of intermolecular interactions in aqueous solutions of poly(vinylmethylether) 
Thermo-responsive materials, such as poly(vinylmethylether) (PVME), attract a common attention because of their unique physical properties resulted from metastable equilibrium between various types of interactions. In this work Monte Carlo (MC) and quantum-mechanical (QM) methods were used to study excluded volume and electrostatic interactions respectively. The graining procedure of PVME-water system was proposed. Its implementation to MC calculations allowed to distinguish how two water fractions differ on dynamics. The QM calculations showed that the formation of cyclic clusters leads to the lengthening of the hydrogen bonds and consequently to higher energies in comparison to linear forms, which is crucial looking at an application of QM results to MC calculation considering thermal interactions.
PMCID: PMC4243001  PMID: 25420704
Cooperative dynamics; Dynamic lattice liquid model; Graining procedure; Monte Carlo methods; Poly(vinylmethylether); Quantum calculations
6.  Calculations of NMR properties for sI and sII clathrate hydrates of methane, ethane and propane 
Calculations of NMR parameters (the absolute shielding constants and the spin-spin coupling constants) for 512, 51262 and 51264 cages enclathrating CH4, C2H6 and C3H8 molecules are presented. The DFT/B3LYP/HuzIII-su3 level of theory was employed. The 13C shielding constants of guest molecules are close to available experimental data. In two cases (the ethane in 512 and the propane in 51262 cages) the 13C shielding constants are reported for the first time. Inversion of the methyl/methylene 13C and 1H shielding constants order is found for propane in the 51262 cage. Topological criteria are used to interpret the changes of values of NMR parameters of water molecules and they establish a connection between single cages and bulk crystal.
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2511-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4236610  PMID: 25408508
Clathrate hydrates; NMR; DFT
7.  Characteristics of protein residue-residue contacts and their application in contact prediction 
Journal of Molecular Modeling  2014;20(11):2497.
Contact sites between amino acids characterize important structural features of a protein. We investigated characteristics of contact sites in a representative set of proteins and their relations between protein class or topology. For this purpose, we used a non-redundant set of 5872 protein domains, identically categorized by CATH and SCOP databases. The proteins represented alpha, beta, and alpha+beta classes. Contact maps of protein structures were obtained for a selected set of physical distances in the main backbone and separations in protein sequences. For each set a dependency between contact degree and distance parameters was quantified. We indicated residues forming contact sites most frequently and unique amino acid pairs which created contact sites most often within each structural class. Contact characteristics of specific topologies were compared to the characteristics of their protein classes showing protein groups with a distinguished contact characteristic. We showed that our results could be used to improve the performance of recent top contact predictor — direct coupling analysis. Our work provides values of contact site propensities that can be involved in bioinformatic databases.
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2497-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4221654  PMID: 25374390
CATH; Contact propensity; Contact sites; Direct coupling analysis; Protein classification; SCOP
8.  Destabilization of the MutSα’s protein-protein interface due to binding to the DNA adduct induced by anticancer agent Carboplatin via molecular dynamics simulations 
Journal of molecular modeling  2013;19(11):10.1007/s00894-013-1998-2.
DNA mismatch repair (MMR) proteins maintain genetic integrity in all organisms by recognizing and repairing DNA errors. Such alteration of hereditary information can lead to various diseases, including cancer. Besides their role in DNA repair, MMR proteins detect and initiate cellular responses to certain type of DNA damage. Its response to the damaged DNA has made the human MMR pathway a useful target for anticancer agents such as carboplatin.
This study indicates that strong, specific interactions at the interface of MutSα in response to the mismatched DNA recognition are replaced by weak, non-specific interactions in response to the damaged DNA recognition. Data suggest a severe impairment of the dimerization of MutSα in response to the damaged DNA recognition. While the core of MutSα is preserved in response to the damaged DNA recognition, the loss of contact surface and the rearrangement of contacts at the protein interface suggest a different packing in response to the damaged DNA recognition.
Coupled in response to the mismatched DNA recognition, interaction energies, hydrogen bonds, salt bridges, and solvent accessible surface areas at the interface of MutSα and within the subunits are uncoupled or asynchronously coupled in response to the damaged DNA recognition.
These pieces of evidence suggest that the loss of a synchronous mode of response in the MutSα’s surveillance for DNA errors would possible be one of the mechanism(s) of signaling the MMR-dependent programed cell death much wanted in anticancer therapies. The analysis was drawn from dynamics simulations.
PMCID: PMC3880575  PMID: 24061854
platinum-DNA adducts carboplatin-induced damage DNA recognition; mismatch repair proteins; MMR; protein-protein interface destabilization; MD simulations
9.  Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups 
Journal of molecular modeling  2013;19(11):5075-5087.
We report an optimized set of CGenFF parameters that can be used to model small molecules containing acylphosphate and N-phosphonosulfonimidoyl functional groups in combination with the CHARMM force field. Standard CGenFF procedures were followed to obtain bonded interaction parameters, which were validated by geometry optimizations, comparison to the results of calculations at the MP2/6-31+G(d) level of theory, and molecular dynamics simulations. In addition, partial atomic charges were assigned so that the energy of hydrogen bonding of the model compounds with water was correctly reproduced. The availability of these parameters will facilitate computational studies of enzymes that generate acyladenylate intermediates during catalytic turnover. In addition, given that the N-phosphonosulfonimidoyl moiety is a stable transition state analog for the reaction of ammonia with an acyladenylate, the parameters developed in this study should find use in efforts to develop novel and potent inhibitors of various glutamine-dependent amidotransferases that have been validated as drug targets. Topology and parameter files for the model compounds used in this study, which can be combined with other CGenFF parameters in computational studies of more complicated acylphosphates and N-phosphonosulfonimidates are made available.
PMCID: PMC3904551  PMID: 24085536
CGenFF; Parameters; Acylphosphates; Sulfoximines; N-Phosphonosulfonimidates; Force Field; Drug Discovery
10.  Distributions of amino acids suggest that certain residue types more effectively determine protein secondary structure 
Journal of molecular modeling  2013;19(10):4337-4348.
Exponential growth in the number of available protein sequences is unmatched by the slower growth in the number of structures. As a result, the development of efficient and fast protein secondary structure prediction methods is essential for the broad comprehension of protein structures. Computational methods that can efficiently determine secondary structure can in turn facilitate protein tertiary structure prediction, since most methods rely initially on secondary structure predictions. Recently, we have developed a fast learning optimized prediction methodology (FLOPRED) for predicting protein secondary structure (S. Saraswathi, et al., [1]). Data are generated by using knowledge-based potentials combined with structure information from the CATH database. A neural network-based extreme learning machine (ELM) and advanced particle swarm optimization (PSO) are used with this data to obtain better and faster convergence to more accurate secondary structure predicted results. A five-fold cross-validated testing accuracy of 83.8 % and a segment overlap (SOV) score of 78.3 % are obtained in this study.
Secondary structure predictions and their accuracy are usually presented for three secondary structure elements: α-helix, β-strand and coil but rarely have the results been analyzed with respect to their constituent amino acids. In this paper, we use the results obtained with FLOPRED to provide detailed behaviors for different amino acid types in the secondary structure prediction. We investigate the influence of the composition, physico-chemical properties and position specific occurrence preferences of amino acids within secondary structure elements. In addition, we identify the correlation between these properties and prediction accuracy. The present detailed results suggest several important ways that secondary structure predictions can be improved in the future that might lead to improved protein design and engineering.
PMCID: PMC4163568  PMID: 23907551
11.  A method for in silico identification of SNAIL/SLUG DNA binding potentials to the E-box sequence using molecular dynamics and evolutionary conserved amino acids 
Journal of molecular modeling  2013;19(9):3463-3469.
Binding of transcription factors to DNA is a dynamic process allowing for spatial- and sequence-specificity. Many methods for determination of DNA-protein structures do not allow for identification of dynamics of the search process, but only a single snap shot of the most stable binding. In order to better understand dynamics of DNA binding, as a protein encounters its cognate site, we have created a computer based DNA scanning array macro which sequentially inserts high affinity DNA consensus binding site at all possible locations in a predicted protein-DNA interface. We show that using short molecular dynamic simulations at each location in the interface, energy minimized states and decreased movement of evolutionary conserved amino acids can be readily observed and used to predict the consensus binding site. This macro is applied to SNAIL class C2H2 zinc finger family proteins. The analysis suggests that 1) SNAIL binds to the E-box in multiple states during encounter with its cognate site; 2) several different amino acids contribute to the E-box binding in each state; 3) the linear array of zinc fingers contributes differentially to overall folding and base-pair recognition, and; 4) each finger may be specialized for stability and sequence specificity. Moreover, the macromolecular movement observed using this dynamic approach may allow the NH2-terminal finger to bind without sequence specificity yet result in higher binding energy. This macro and overall approach could be applicable to many evolutionary conserved transcription factor families and should help elucidate better the varied mechanisms used for DNA sequence specific binding.
PMCID: PMC3745821  PMID: 23708613
SNAIL; zinc finger recognition; E-box binding; transcription factor binding; protein-DNA dynamics
12.  Allosteric transition and binding of small molecule effectors causes curvature change in central β-sheets of selected enzymes 
Journal of molecular modeling  2010;17(4):899-911.
A quantitative description of allosteric transition remains a significant science challenge. Many allosteric enzymes contain a central β-sheet in their catalytic domain. When an allosteric protein undergoes the transition between T (tense) and R (relaxed) allosteric states, this central β-sheet undergoes a conformational change. A traditional method of measuring this change, the root mean square deviation (RMSD), appears to be inadequate to describe such changes in meaningful quantitative manner. We designed a novel quantitative method to demonstrate this conformational transition by measuring the change in curvature of the central β-sheet when enzymes transition between allosteric states. The curvature was established by calculating the semiaxes of a 3-D hyperboloid fitted by least squares to the Cα atomic positions of the β-sheet. The two enzymes selected for this study, fructose 1,6-bisphosphatase (FBPase) from pig kidney and aspartate carbamoyltransferase (ATCase) from E. coli, showed while transitioning between the allosteric states (T ⇔ R) a notable change in β-sheet curvature (∼5%) that results in a large lateral shift at the sheet's edge, which is necessary to convey the signal. The results suggest that the β-sheet participates in storing elastic energy associated with the transition. Establishing a tentative link between the energetics of the β-sheet in different allosteric states provides a more objective basis for the naming convention of allosteric states (tense or relaxed), and provides insight into the hysteretic nature of the transition. The approach presented here allows for a better understanding of the internal dynamics of allosteric enzymes by defining the domains that directly participate in the transition.
PMCID: PMC4127431  PMID: 20602244
Allosteric transition; β-sheet; Conformational change; Nonlinear fitting; Fructose 1; 6-bisphosphatase; Aspartate transcarbamylase; Global optimization
13.  Effects of Local Protein Environment on the Binding of Diatomic Molecules to Heme in Myoglobins. DFT and Dispersion-Corrected DFT Studies 
Journal of molecular modeling  2013;19(8):3307-3323.
The heme-AB binding energies (AB = CO, O2) in a wild-type myoglobin (Mb) and two mutants (H64L, V68N) of Mb have been investigated in detail with both DFT and dispersioncorrected DFT methods, where H64L and V68N represent two different, opposite situations. Several dispersion correction approaches were tested in the calculations. The effects of the local protein environment were accounted for by including the five nearest surrounding residues in the calculated systems. The specific role of histidine-64 in the distal pocket was examined in more detail in this study than in other studies in the literature. Although the present calculated results do not change the previous conclusion that the hydrogen bonding by the distal histidine-64 residue plays a major role in the O2/CO discrimination by Mb, more details about the interaction between the protein environment and the bound ligand have been revealed in this study by comparing the binding energies of AB to a porphyrin and the various myoglobins. The changes in the experimental binding energies from one system to another are well reproduced by the calculations. Without constraints on the residues in geometry optimization, the dispersion correction is necessary, since it improves the calculated structures and energetic results significantly.
PMCID: PMC3726265  PMID: 23661270
DFT calculations; dispersion correction; myoglobins; carbon monoxide; oxygen
14.  Evidence supporting the existence of a NUPR1-like family of helix-loop-helix chromatin proteins related to, yet distinct from, AT hook-containing HMG proteins 
Journal of Molecular Modeling  2014;20(8):2357.
NUPR1, a small chromatin protein, plays a critical role in cancer development, progression, and resistance to therapy. Here, using a combination of structural bioinformatics and molecular modeling methods, we report several novel findings that enhance our understanding of the biochemical function of this protein. We find that NUPR1 has been conserved throughout evolution, and over time it has undergone duplications and transpositions to form other transcriptional regulators. Using threading, homology-based molecular modeling, molecular mechanics calculations, and molecular dynamics simulations, we generated structural models for four of these proteins: NUPR1a, NUPR1b, NUPR2, and the NUPR-like domain of GTF2-I. Comparative analyses of these models combined with extensive linear motif identification reveal that these four proteins, though similar in their propensities for folding, differ in size, surface changes, and sites amenable for posttranslational modification. Lastly, taking NUPR1a as the paradigm for this family, we built models of a NUPR–DNA complex. Additional structural comparisons revealed that NUPR1 defines a new family of small-groove-binding proteins that share structural features with, yet are distinct from, helix-loop-helix AT-hook-containing HMG proteins. These models and inferences should lead to a better understanding of the function of this group of chromatin proteins, which play a critical role in the development of human malignant diseases.
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2357-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4139591  PMID: 25056123
DNA-binding proteins; NUPR1; Molecular dynamics; High Mobility Group (HMG)
15.  Substituent effects in hydrogen bonding: DFT and QTAIM studies on acids and carboxylates complexes with formamide 
Journal of Molecular Modeling  2014;20(8):2356.
Four series of hydrogen bonded complexes of formamide and substituted benzoic acids and benzoates were studied in the light of substituent effect on intermolecular interactions. The analysis based on energy of interaction, geometry, QTAIM-derived properties of hydrogen bond critical point and energy of hydrogen bonds were made and discussed. The opposite effect of the substituent on hydrogen bond donor and acceptor in acid series was found and analyzed. The isodesmic reactions were used to further study the interaction preferences.
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2356-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4139586  PMID: 25024009
Cooperativity; Hydrogen bonding; QTAIM theory; Substituent effect; Weak interactions
16.  Conformational space and vibrational spectra of 2-[(2,4-dimethoxyphenyl)amino]-1,3-thiazolidin-4-one 
Journal of Molecular Modeling  2014;20(8):2366.
In this work we present the results of a study of the X-ray structure of 2-[(2,4-dimethoxyphenyl)amino]-1,3-thiazolidin-4-one. Using the FTIR spectra in solid state and results of ab initio calculations we explain the issue of the tautomerism of this molecule. The compound is shown to exist as the 2-amino tautomer rather 2-imino tautomer. Here we consider eight possible tautomers. On the basis of the vibrational spectra we can eliminate five possible tautomers, as not existing in the solid state. As the most possible tautomeric form we have found keto 2-amino form.
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2366-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4139587  PMID: 25024010
ab initio calculations; FTIR spectral characteristics; Tautomerism; 1,3-thiazolidin-4-one; X-ray analysis
17.  A unified coarse-grained model of biological macromolecules based on mean-field multipole–multipole interactions 
Journal of Molecular Modeling  2014;20(8):2306.
A unified coarse-grained model of three major classes of biological molecules—proteins, nucleic acids, and polysaccharides—has been developed. It is based on the observations that the repeated units of biopolymers (peptide groups, nucleic acid bases, sugar rings) are highly polar and their charge distributions can be represented crudely as point multipoles. The model is an extension of the united residue (UNRES) coarse-grained model of proteins developed previously in our laboratory. The respective force fields are defined as the potentials of mean force of biomacromolecules immersed in water, where all degrees of freedom not considered in the model have been averaged out. Reducing the representation to one center per polar interaction site leads to the representation of average site–site interactions as mean-field dipole–dipole interactions. Further expansion of the potentials of mean force of biopolymer chains into Kubo’s cluster-cumulant series leads to the appearance of mean-field dipole–dipole interactions, averaged in the context of local interactions within a biopolymer unit. These mean-field interactions account for the formation of regular structures encountered in biomacromolecules, e.g., α-helices and β-sheets in proteins, double helices in nucleic acids, and helicoidally packed structures in polysaccharides, which enables us to use a greatly reduced number of interacting sites without sacrificing the ability to reproduce the correct architecture. This reduction results in an extension of the simulation timescale by more than four orders of magnitude compared to the all-atom representation. Examples of the performance of the model are presented.
FigureComponents of the Unified Coarse Grained Model (UCGM) of biological macromolecules
PMCID: PMC4139597  PMID: 25024008
Coarse-graining; Mean-field approach; Multipole–multipole interactions; Proteins; Nucleic acids; Polysaccharides
18.  Apparent basicities of the surfaces characterizing the dominant crystal habits of distinct polymorphic forms of 4-aminosulfonamide 
Journal of Molecular Modeling  2014;20(7):2276.
A new approach for estimating local basicities/acidities of groups exposed on crystal surfaces was formulated and validated. The model, constructed within a quantitative structure–property relationship (QSPR) framework, allowed the expression of the protonic properties of amine and sulfonamide groups as functions of simple molecular descriptors of geometric types. This enabled the application of a QM/MM approach for the structural optimization of SNM molecules located on the surfaces of the dominant crystal habits. The obtained pKa values were used for classification of the protonic properties of four p-aminosulfonamide (SNM) polymorphs. The computed distributions of the surface pKa values suggested that, for all polymorphs, the amino group has statistically the same proton-accepting ability on the crystal surface as in bulk water solution. Although sulfonamide groups on the crystal surface—especially those distributed on β- and γ-dominant faces—seem to be more acidic compared to bulk water solution, the pKa values are statistically indistinguishable irrespective of the morphology. This suggests that experimentally observed differences in the perichromic properties of SNM polymorphs do not arise from local pH changes, Thus, apparent local basicities are to be relaed to structural similarity of SNM surfaces and thymol blue conformers anabling direct interactions.
FigureExperimentally observed differences in the perichromic properties of p-aminosulfonamide polymorphs are structural in origin; they are not due to local pH changes
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2276-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4107284  PMID: 24935108
Polymorph; Morphology; Sulfonamide drugs; Morphology growth; Chromogenic molecular probe; Thymol blue
19.  Intermediate electrostatic field for the elongation method 
A simple way to improve the accuracy of the fragmentation methods is proposed. The formalism was applied to the elongation (ELG) method at restricted open-shell Hartree-Fock (ROHF) level of theory. The α-helix conformer of polyglycine was taken as a model system. The modified ELG method includes a simplified electrostatic field resulting from point-charge distribution of the system’s environment. In this way the long-distance polarization is approximately taken into account. The field attenuates during the ELG process to eventually disappear when the final structure is reached. The point-charge distributions for each ELG step are obtained from charge sensitivity analysis (CSA) in force-field atoms resolution. The presence of the intermediate field improves the accuracy of ELG calculations. The errors in total energy and its kinetic and potential contributions are reduced by at least one-order of magnitude. In addition the SCF convergence of ROHF scheme is improved.
PMCID: PMC4072069  PMID: 24878802
Charge sensitivity analysis; Electronegativity equalization equations; Elongation cutoff method; Elongation method; Population analyses; Order-N methods
20.  On the origin of internal rotation in ammonia borane 
The internal rotation in ammonia borane (AB) was studied on the basis of natural orbitals for chemical valence (NOCV) and eigenvectors for Pauli repulsion (NOPR). We found that the total hyperconjugation stabilization (ca. 5 kcal mol−1), based on the charge transfer from the occupied σ (B–H) orbitals into the empty σ*(N–H), slightly favors the staggered conformation over the eclipsed one; however, the barrier to internal rotation in ammonia borane can be understood predominantly in a ‘classical’ way, as originating from the steric (Pauli) repulsion contributions (of the kinetic origin) that act solely between N–H and B–H bonds. Repulsion between the lone pair of ammonia and the adjacent B–H bonds was found to be dominant in absolute terms; however, it does not determine the rotational barrier. Similar conclusions on the role of CH↔HC repulsion appeared to be valid for isoelectronic ethane.
FigurePauli (kinetic) repulsion acting between the N-H and B-H bonds of ammonia borane
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2272-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4072093  PMID: 24863530
Ammonia borane; Steric repulsion; Hyperconjugation
21.  Geometric consequences of electron delocalization for adenine tautomers in aqueous solution 
Journal of Molecular Modeling  2014;20(6):2234.
Geometric consequences of electron delocalization were studied for all possible adenine tautomers in aqueous solution by means of ab initio methods {PCM(water)//DFT(B3LYP)/6-311+G(d,p)} and compared to those in the gas phase {DFT(B3LYP)/6-311+G(d,p)}. To measure the consequences of any type of resonance conjugation (π-π, n-π, and σ-π), the geometry-based harmonic oscillator model of electron delocalization (HOMED) index, recently extended to the isolated (DFT) and hydrated (PCM//DFT) molecules, was applied to the molecular fragments (imidazole, pyrimidine, 4-aminopyrimidine, and purine) and also to the whole tautomeric system. For individual tautomers, the resonance conjugations and consequently the bond lengths strongly depend on the position of the labile protons. The HOMED indices are larger for tautomers (or their fragments) possessing the labile proton(s) at the N rather than C atom. Solvent interactions with adenine tautomers slightly increase the resonance conjugations. Consequently, they slightly shorten the single bonds and lengthen the double bonds. When going from the gas phase to water solution, the HOMED indices increase (by less than 0.15 units). There is a good relation between the HOMED indices estimated in water solution and those in the gas phase for the neutral and ionized forms of adenine. Subtle effects, being a consequence of intramolecular interactions between the neighboring groups, are so strongly reduced by solvent that the relation between the HOMED indices and the relative energies for the neutral adenine tautomers seems to be better in water solution than in the gas phase.
FigureThe total HOMED indices in water solution correlate well with those in the gas phase for the neutral and charged isomers of adenine
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2234-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4072068  PMID: 24842324
Adenine; Electron delocalization; HOMED/ΔE relation; PCM//DFT; Solvent effects; Tautomers
22.  Probing the global and local dynamics of aminoacyl-tRNA synthetases using all-atom and coarse-grained simulations 
Journal of Molecular Modeling  2014;20(5):2245.
Coarse-grained simulations have emerged as invaluable tools for studying conformational changes in biomolecules. To evaluate the effectiveness of computationally inexpensive coarse-grained models in studying global and local dynamics of large protein systems like aminoacyl-tRNA synthetases, we have performed coarse-grained normal mode analysis, as well as principle component analysis on trajectories of all-atom and coarse-grained molecular dynamics simulations for three aminoacyl-tRNA synthetases—Escherichia coli methionyl-tRNA synthetase, Thermus thermophilus leucyl-tRNA synthetase, and Enterococcus faecium prolyl-tRNA synthetase. In the present study, comparison of predicted dynamics based on B-factor and overlap calculations revealed that coarse-grained methods are comparable to the all-atom simulations in depicting the intrinsic global dynamics of the three enzymes. However, the principal component analyses of the motions obtained from the all-atom molecular dynamics simulations provide a superior description of the local fluctuations of these enzymes. In particular, the all-atom model was able to capture the functionally relevant substrate-induced dynamical changes in prolyl-tRNA synthetase. The alteration in the coupled dynamics between the catalytically important proline-binding loop and its neighboring structural elements due to substrate binding has been characterized and reported for the first time. Taken together, the study portrays comparable and contrasting situations in studying the functional dynamics of large multi-domain aminoacyl-tRNA synthetases using coarse-grained and all-atom simulation methods.
FigureSubstrate-induced conformational change in E. facium prolyl-tRNA synthetase
Electronic supplementary material
The online version of this article (doi:10.1007/s00894-014-2245-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4030129  PMID: 24810463
Aminoacyl-tRNA synthetase; Coarse-grained simulations; Intrinsic global dynamics; Molecular dynamics; Normal model analysis; Protein dynamics
23.  Electronic polarization stabilizes tertiary structure prediction of HP-36 
Journal of Molecular Modeling  2014;20(4):2195.
Molecular dynamic (MD) simulations with both implicit and explicit solvent models have been carried out to study the folding dynamics of HP-36 protein. Starting from the extended conformation, the secondary structure of all three helices in HP-36 was formed in about 50 ns and remained stable in the remaining simulation. However, the formation of the tertiary structure was difficult. Although some intermediates were close to the native structure, the overall conformation was not stable. Further analysis revealed that the large structure fluctuation of loop and hydrophobic core regions was devoted mostly to the instability of the structure during MD simulation. The backbone root-mean-square deviation (RMSD) of the loop and hydrophobic core regions showed strong correlation with the backbone RMSD of the whole protein. The free energy landscape indicated that the distribution of main chain torsions in loop and turn regions was far away from the native state. Starting from an intermediate structure extracted from the initial AMBER simulation, HP-36 was found to generally fold to the native state under the dynamically adjusted polarized protein-specific charge (DPPC) simulation, while the peptide did not fold into the native structure when AMBER force filed was used. The two best folded structures were extracted and taken into further simulations in water employing AMBER03 charge and DPPC for 25 ns. Result showed that introducing polarization effect into interacting potential could stabilize the near-native protein structure.
PMCID: PMC3996369  PMID: 24715046
Molecular dynamics; Polarization effect; Protein folding; Solvent model
24.  3D-dynamic representation of DNA sequences 
Journal of Molecular Modeling  2014;20(3):2141.
A new 3D graphical representation of DNA sequences is introduced. This representation is called 3D-dynamic representation. It is a generalization of the 2D-dynamic dynamic representation. The sequences are represented by sets of “material points” in the 3D space. The resulting 3D-dynamic graphs are treated as rigid bodies. The descriptors characterizing the graphs are analogous to the ones used in the classical dynamics. The classification diagrams derived from this representation are presented and discussed. Due to the third dimension, “the history of the graph” can be recognized graphically because the 3D-dynamic graph does not overlap with itself. Specific parts of the graphs correspond to specific parts of the sequence. This feature is essential for graphical comparisons of the sequences. Numerically, both 2D and 3D approaches are of high quality. In particular, a difference in a single base between two sequences can be identified and correctly described (one can identify which base) by both 2D and 3D methods.
PMCID: PMC3964303  PMID: 24567158
Descriptors; DNA sequences; Moments of inertia
25.  Nanomechanics of β-rich proteins related to neuronal disorders studied by AFM, all-atom and coarse-grained MD methods 
Journal of Molecular Modeling  2014;20(3):2144.
Computer simulations of protein unfolding substantially help to interpret force-extension curves measured in single-molecule atomic force microscope (AFM) experiments. Standard all-atom (AA) molecular dynamics simulations (MD) give a good qualitative mechanical unfolding picture but predict values too large for the maximum AFM forces with the common pulling speeds adopted here. Fine tuned coarse-grain MD computations (CG MD) offer quantitative agreement with experimental forces. In this paper we address an important methodological aspect of MD modeling, namely the impact of numerical noise generated by random assignments of bead velocities on maximum forces (Fmax) calculated within the CG MD approach. Distributions of CG forces from 2000 MD runs for several model proteins rich in β structures and having folds with increasing complexity are presented. It is shown that Fmax have nearly Gaussian distributions and that values of Fmax for each of those β-structures may vary from 93.2 ± 28.9 pN (neurexin) to 198.3 ± 25.2 pN (fibronectin). The CG unfolding spectra are compared with AA steered MD data and with results of our AFM experiments for modules present in contactin, fibronectin and neurexin. The stability of these proteins is critical for the proper functioning of neuronal synaptic clefts. Our results confirm that CG modeling of a single molecule unfolding is a good auxiliary tool in nanomechanics but large sets of data have to be collected before reliable comparisons of protein mechanical stabilities are made.
FigureComputational strechnings of single protein modeules leads to broad distributions of unfolding forces
PMCID: PMC3964301  PMID: 24562857
Atomic force microscopy; β-rich domains; Coarse-grained simulations; Contactin; Fibronectin; Gō-like model; Mechanical stretching of proteins; Neurexin; Steered molecular dynamics

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