Optimization of cutting schemes for the evaluation of molecular electrostatic potentials in proteins via Moving-Domain QM/MM

This work presents new developments of the moving-domain QM/MM (MoD-QM/MM) method for modeling protein electrostatic potentials. The underlying goal of the method is to map the electronic density of a specific protein configuration into a point-charge distribution. Important modifications of the general strategy of the MoD-QM/MM method involve new partitioning and fitting schemes and the incorporation of dynamic effects via a single-step free energy perturbation approach (FEP). Selection of moderately sized QM domains partitioned between and C (from C=O), with incorporation of delocalization of electrons over neighboring domains, results in a marked improvement of the calculated molecular electrostatic potential (MEP). More importantly, we show that the evaluation of the electrostatic potential can be carried out on a dynamic framework by evaluating the free energy difference between a non-polarized MEP and a polarized MEP. A simplified form of the potassium ion channel protein Gramicidin-A from Bacillus brevis is used as the model system for the calculation of MEP. Figure Schematic representation of the Moving Domain QM/MM method     

Characterization of a complete cycle of acetylcholinesterase catalysis by <Emphasis Type="Italic">ab initio</Emphasis> QM/MM modeling

The reaction mechanism of acetylcholine hydrolysis by acetylcholinesterase, including both acylation and deacylation stages from the enzyme-substrate (ES) to the enzyme-product (EP) molecular complexes, is examined by using an ab initio type quantum mechanical – molecular mechanical (QM/MM) approach. The density functional theory PBE0/aug-6–31+G* method for a fairly large quantum part trapped inside the native protein environment, and the AMBER force field parameters in the molecular mechanical part are employed in computations. All reaction steps, including the formation of the first tetrahedral intermediate (TI1), the acylenzyme (EA) complex, the second tetrahedral intermediate (TI2), and the EP complex, are modeled at the same theoretical level. In agreement with the experimental rate constants, the estimated activation energy barrier of the deacylation stage is slightly higher than that for the acylation phase. The critical role of the non-triad Glu202 amino acid residue in orienting lytic water molecule and in stabilizing the second tetrahedral intermediate at the deacylation stage of the enzymatic process is demonstrated. Figure The computed energy diagram for the reaction path from the enzyme – substrate complex (ES) to the enzyme-product complex (EP).     

Oxidation mechanism in the metabolism of (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide on oxyferryl active site in CYP3A4 Cytochrome: DFT modeling

The metabolism mechanism of (S)-N-[1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide, mediated by CYP3A4 Cytochrome has been investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. Two different orientations of phenyl ring for substrate approach toward oxyferryl center, imposing two subsequent rearrangement pathways have been investigated. Starting from σ-complex in perpendicular orientation enzymatic mechanism involves consecutive proton shuttle intermediate, which further leads to the formation of alcohol and ketone. Parallel conformation leads solely to ketone product by 1,2 hydride shift. Although parallel and perpendicular σ-complexes are energetically equivalent both for the gas phase or PCM solvent model, molecular dynamics studies in full CYP3A4 environment show that perpendicular conformation of the σ-complex should be privileged, stabilized by hydrophobic interactions of phenylacrylamide chain. After assessing probability of the two conformations we postulate that the alcohol, accessible with the lowest energy barriers should be the major metabolite for studied substrate and CYP3A4 enzyme. Figure Orientation of phenyl ring towards porphyrin plane selected by substrate interaction with enzymatic cavity channels enzymatic reaction     

AMBER force-field parameters for phosphorylated amino acids in different protonation states: phosphoserine, phosphothreonine, phosphotyrosine, and phosphohistidine

We report a consistent set of AMBER force-field parameters for the most common phosphorylated amino acids, phosphoserine, phosphothreonine, phosphotyrosine, and phosphohistidine in different protonation states. The calculation of atomic charges followed the original restrained electrostatic potential fitting procedure used to determine the charges for the parm94/99 parameter set, taking α-helical and β-strand conformations of the corresponding ACE-/NME-capped model peptide backbone into account. Missing force-field parameters were taken directly from the general AMBER force field (gaff) and the parm99 data set with minor modifications, or were newly generated based on ab initio calculations for model systems. Final parameters were validated by geometry optimizations and molecular-dynamics simulations. Template libraries for the phosphorylated amino acids in Leap format and corresponding frcmod parameter files are made available. Figure Schematic illustration of the systems used for parameter generation. Acid hydrogens are shown in red Electronic Supplementary Material Supplementary material is available for this article at     

Investigation of the intermolecular proton transfer in the supersystems adenine-methanol/ethanol/i-propanol: MP2 and DFT levels study

Twelve H-bonded supersystems constructed between the adenine tautomers and methanol, ethanol, and i-propanol were studied at the B3LYP and MP2 levels of theory using 6-311G(d,p) and 6-311++G(d,p) basis functions. The thermodynamic parameters of the complex formations were calculated in order to estimate the exact stability of the supersystems. It was proven that the calculated energy barriers of the alcohol-assisted proton transfers are about 60% lower than those of the intramolecular proton transfers in adenine found earlier (Gu and Leszczynski in J Phys Chem A 103:2744–2750, 1999). Figure H-bonded complex between i-propanol and adenine     

Ab initio calculations on the thermodynamic properties of azaborospiropentanes

Following our recent studies of the thermodynamic properties of azaspiropentane and borospiropentane, in consideration of their usefulness as new potential high energy materials, we follow up with ab initio calculations on the thermodynamic properties of azaborospiropentanes. Properties reported in this study include optimized structural parameters, vibrational frequencies, enthalpies of formation, specific enthalpies of combustion, proton affinities, and hydride affinities. Our results indicate that azatriborospiropentane gives off most energy when combusted, as evidenced by its specific enthalpy of combustion of about −52 kJ per gram. Figure Optimized geometry for R-azatriborospiropentane (10) Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Continuous metadynamics in essential coordinates as a tool for free energy modelling of conformational changes

Modelling of conformational changes in biopolymers is one of the greatest challenges of molecular biophysics. Metadynamics is a recently introduced free energy modelling technique that enhances sampling of configurational (e.g. conformational) space within a molecular dynamics simulation. This enhancement is achieved by the addition of a history-dependent bias potential, which drives the system from previously visited regions. Discontinuous metadynamics in the space of essential dynamics eigenvectors (collective motions) has been proposed and tested in conformational change modelling. Here, we present an implementation of two continuous formulations of metadynamics in the essential subspace. The method was performed in a modified version of the molecular dynamics package GROMACS. These implementations were tested on conformational changes in cyclohexane, alanine dipeptide (terminally blocked alanine, Ace-Ala-Nme) and SH3 domain. The results illustrate that metadynamics in the space of essential coordinates can accurately model free energy surfaces associated with conformational changes. Figure The conformational free energy surface of cyclohexane in the space of the two most intensive collective motions.

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Theoretical study of the hydrogen-bonded complexes serotonin–water/hydrogen peroxide

Eight H-bonded complexes between serotonin (5-hydroxy-tryptamine) and water/hydrogen peroxide were studied at the B3LYP and HF levels of theory, using the 6-31+G(d) basis set. A thermodynamic analysis was performed in order to find the most stable complex. The calculated bonding parameters showed that the most stable H-bonded complex is formed between serotonin and hydrogen peroxide by means of the intermolecular H-bond –H₂N...H–OOH. Fig. a Theoretical study of the hydrogen-bonded supersystems serotonin-water/hydrogen peroxide     

Theoretical studies on the molecular structure and vibrational spectra of some dimethyl substituted pyridine derivatives

The molecular geometries, normal mode frequencies, intensities and corresponding infrared assignments of monomeric and dimeric 2,3-dimethylpyridine, 2,4-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine and monomeric 2,6-dimethylpyridine in the ground state were investigated at the density functional theory (DFT)-B3LYP level using the 6-311+G(d, p) basis set. The vibrational frequencies and geometric parameters of C–H stretching and bending in the fundamental region were calculated and compared to the Fourier transform infrared (FT-IR) data obtained. In the studied monomeric and dimeric dimethyl substituted pyridine derivatives, the C–H stretching and bending frequency shifts that occur between the dimer and the monomer may be diagnostic of the magnitude of dimerization energy. As supported by data in the literature, the most stable dimeric form was obtained for the 3,4-dimethylpyridine molecule. Figure Molecular model and numbering scheme of the studied dimeric dimethylpyridinederivatives     

Structural insights into the effect of isonucleosides on B-DNA duplexes using molecular-dynamics simulations

Some structural insights into the conformations of the isonucleosides containing duplexes have been provided. Unrestrained molecular-dynamics simulations on 18-mer duplexes with isonucleosides incorporated at the 3'-end or in the center of one strand have been carried out with explicit solvent under periodic boundary conditions using the AMBER force field and the particle mesh Ewald method. The Watson–Crick hydrogen-bonding patterns of the duplexes studied remained intact throughout the simulation. For the modified duplexes, the changes observed in the inter-base pair parameters and backbone torsional angles were primarily localized at the isonucleoside-inserted area. All five structures studied remained in the B-form family. The decreased stacking abilities indicated by the large changes in inter-base pair parameters and the large changes in backbones made the modified duplexes show a minor thermal destabilization in comparison with native DNA. The MM_PBSA method for estimating binding free energies on two complementary strands was used. The results showed that the binding free energies of isonucleoside-incorporated DNA duplexes were lower than the native DNA duplex, which is in good agreement with experimental observations.      

TCNE-aniline charge transfer complex: ab initio and TDDFT investigations in gas phase

The geometric and electronic structure of tetracyanoethylene (TCNE)-aniline (donor-acceptor type) complex has been investigated in gas phase using ab initio and time dependent density functional theory calculations. Both the above calculations predict a composed structure for the complex, in which the interacting site is a C≡N and C=C bond center in the TCNE and, –NH₂ and π-electrons of aniline. The N atom of aniline is oriented toward the TCNE molecule. The charge transfer transition energy, estimated by calculating the ground-to-excited state transition electric dipole moments of the complex, agree well with the reported experimental value in chloroform medium. TCNE-aniline at ground state. TCNE-aniline at excited state     

G2, G3, and complete basis set calculations of the thermodynamic properties of cis- and trans-triazene

Following our recent study on triazane, we present a follow-up study on the thermodynamic properties of triazane’s unsaturated analog, triazene. We predict optimized structural parameters, vibrational frequencies, enthalpies of formation, enthalpies of combustion, specific enthalpies of combustion, and proton affinities. Our results indicate that the cis form of triazene has a specific enthalpy of combustion of −15.2 kJ g⁻¹ and the trans form has a specific enthalpy of combustion of −14.7 kJ g⁻¹. Figure Structures of cis- and trans-triazane, N₃H₃     

Interactions in pseudorotoxanes based on crown ether-secondary ammonium motifs. A theoretical study

A theoretical analysis of the nature of the interactions in dibenzo[24]crown-8 (DB24C8)-n-dibutylammonium (DBM)—pseudorotaxane complex at the MP2 and DFT levels shows that the main contribution to the binding energy is the electrostatic interaction with moderate (20–25%) correlation stabilization. The total binding energy in the DB24C8-DBM complex represents a sum of the binding energies of two NH–O and one CH–O hydrogen bonds and the latter constitutes about 25% of the total interaction energy, giving the total binding energy of −41.2 kcal mol⁻¹ at the BHandHLYP/6-311++G** level. Deprotonation of the DB24C8-DBM complex reduces the binding energy by some 50 kcal mol⁻¹, giving metastable complexes DB24C8-DBA-1 or DB24C8-DBA-2, which will dissociate to give free crown ether and n-dibutylamine because of the strong exchange repulsion that prevails in neutral complexes. Figure Formation of DB24C8-DBM pseudorotoxane complex     

Theoretical study of the intermolecular H-bonding and intermolecular proton transfer between isocytosine tautomeric forms and <Emphasis Type="Italic">R</Emphasis>,<Emphasis Type="Italic">S</Emphasis>-lactic acid

Eight H-bonded complexes between isocytosine (isoC) tautomeric forms and R/S-lactic acid (LA) have been studied at the B3LYP and HF levels of theory using 6–31+G(d) basis set. The energy barriers of the intermolecular proton transfers were also estimated as the results showed that they are several times lower than those of the intramolecular proton transfers of isoC in the gas phase. Furthermore, the energy barriers of the tautomerizations in which the carboxylic H-atom takes part are several times lower than those in which the LA OH group assists the proton transfer. Figure     

The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P<Superscript>III</Superscript>)

Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (P^III). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that decomposition to P^III derivatives proceeds via an elimination reaction. Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P^III)     

ONIOM DFT/PM3 calculation on the interaction between STI-571 and abelson tyrosine kinase

The ONIOM2 (B3LYP/6–31G (d, p): PM3) and B3LYP/6–31G (d, p) methods were applied to investigate the interaction between STI-571 and abelson tyrosine kinase binding site. The complex of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- phenyl]-benzamide (part of STI-571) and related 16 amino acid residues were found at B3LYP/6–31G (d, p) level to have hydrogen bonds and π....π stacking interaction, their binding energy via HAF optimization was −20.4 kcal mol⁻¹. The results derived from this study agreed well with the reported observation. Figure Optimized structure of STI-571 and Thr315 in abelson tyrosine kinase based on ONIOM2 method     

Reverse-docking study of the TADDOL-catalyzed asymmetric hetero-Diels–Alder reaction

The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels–Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis. Each pose is scored and ranked based on its molecular-mechanics docking energy. The reverse-docking procedure reveals a clear energetic trend in favor of the experimentally preferred product enantiomers. Analysis of the best poses suggests a geometric model that is consistent with principles of molecular recognition, catalysis, and experimental data.      

Ab initio analysis of the Cope rearrangement of germacrane sesquiterpenoids

The energetics of the Cope rearrangement of 17 germacrane sesquiterpenoids to their respective elemane forms have been calculated using both density functional theory (B3LYP/6-31G*) and post Hartee-Fock (MP2/6-31G**) ab initio methods. The calculations are in qualitative agreement with experimentally observed Cope rearrangements, but the two methods give slightly different results. MP2 calculations generally show more favorable elemene energies compared to the respective germacrenes (by around 3–4 kcal mol⁻¹) and smaller activation energies (by 2–3 kcal mol⁻¹). Additionally, neither method is accurate enough to consistently reproduce the germacrene/elemene equilibrium. Apparently, the generally small energy differences between the two forms in these sesquiterpenoids cannot be adequately reproduced at these levels of calculation. Figure The Cope rearrangement of the germacrane sesquiterpenoid bacchascandon to the elemane shyobunone     

G2, G3, and complete basis set calculations on the thermodynamic properties of triazane

As a follow-up study to our study on tetrazane (N₄H₆), we present computed thermodynamic properties of triazane (N₃H₅). Calculated properties include optimized geometries, infrared vibrations, enthalpy of formation, enthalpy of combustion, and proton affinities. We have also mapped the potential energy surface as the molecule is rotated about the N-N bond. We have predicted a specific enthalpy of combustion for triazane of about -20 kJ g⁻¹. Figure Schematic diagram of the dielectric barrier discharge (left) and typical temporal profiles of voltage and current, as obtained from the simulations (right)     

Density functional computations of enantioselective alkynylation of aldehyde catalyzed by chiral zinc(II)-complexes

The enantioselective alkynylation of aldehyde catalyzed by chiral zinc(II)-complexes was studied by means of the density functional theory (DFT). All the structures were optimized completely at the B3LYP/6-31G(d,p) level. To obtain more exact energies, single-point energy calculations at B3LYP/6-31+G(d,p) level were carried out on the B3LYP/6-31G(d,p) geometries. As shown, this enantioselective alkynylation was endothermic. The chirality-determining step for the alkynylation was the formation of the catalyst–ethanol complexes and the transition states for this step involved a six-membered ring. The dominant products predicted theoretically were of (R)-chirality, in good agreement with experiment.