Motor-like Properties of Nonmotor Enzymes

Molecular motors are thought to generate force and directional motion via nonequilibrium switching between energy surfaces. Because all enzymes can undergo such switching, we hypothesized that the ability to generate rotary motion and torque is not unique to highly adapted biological motor proteins but is instead a common feature of enzymes. We used molecular dynamics simulations to compute energy surfaces for hundreds of torsions in three enzymes—adenosine kinase, protein kinase A, and HIV-1 protease—and used these energy surfaces within a kinetic model that accounts for intersurface switching and intrasurface probability flows. When substrate is out of equilibrium with product, we find computed torsion rotation rates up ～140 cycles s^?1, with stall torques up to ～2 kcal mol^?1 cycle^?1, and power outputs up to ～50 kcal mol^?1 s^?1. We argue that these enzymes are instances of a general phenomenon of directional probability flows on asymmetric energy surfaces for systems out of equilibrium. Thus, we conjecture that cyclic probability fluxes, corresponding to rotations of torsions and higher-order collective variables, exist in any chiral molecule driven between states in a nonequilibrium manner; we call this the “Asymmetry-Directionality” conjecture. This is expected to apply as well to synthetic chiral molecules switched in a nonequilibrium manner between energy surfaces by light, redox chemistry, or catalysis.     

Theoretical study of chemisorption of cyanuric fluoride and S-triazine on the surface of Al-doped graphene

We studied the adsorption of cyanuric fluoride (CF) and s-triazine (ST) molecules on the surface of pristine as well as Al-doped graphenes using density functional theory calculations. Our results reveal low adsorption on the surface of pristine graphene; but by modification of surface using aluminium, resulted Al-doped graphene becomes more reactive towards both CF and ST molecules. We aimed to focus on the adsorption energy, electronic structure, charge analysis, density of state and global indices of each system upon adsorption of CF and ST molecules on the above-mentioned surfaces. Our calculated adsorption energies for the most stable position configurations of CF and ST on Al-doped graphene were ?76.53 kJ mol^?1 (?57.45 kJ mol^?1 BSSE corrected energy) and ?115.55 kJ mol^?1 (?86.87 kJ mol^?1 BSSE corrected energy), respectively, which point to the chemisorption process. For each CF and ST molecule, upon adsorption on the surface of Al-doped graphene, the band gap of HOMO-LUMO was reduced considerably and it becomes a p-type semiconductor, whereas there is no hybridisation between the above-mentioned molecules and pristine graphene.     

Theoretical studies of the interaction between enflurane and water

Increase of the atmospheric concentration of halogenated organic compounds is partially responsible for a change of the global climate. In this work we have investigated the interaction between halogenated ether and water, which is one of the most important constituent of the atmosphere. The structures of the complexes formed by the two most stable conformers of enflurane (a volatile anaesthetic) with one and two water molecules were calculated by means of the counterpoise CP-corrected gradient optimization at the MP2/6–311++G(d,p) level. In these complexes the CH…O_w hydrogen bonds are formed, with the H…O_w distances varying between 2.23 and 2.32 Å. A small contraction of the CH bonds and the blue shifts of the ν(CH) stretching vibrations are predicted. There is also a weak interaction between one of the F atoms and the H atom of water, with the H_w…F distances between 2.41 and 2.87 Å. The CCSD(T)/CBS calculated stabilization energies in these complexes are between ?5.89 and ?4.66 kcal?mol^?1, while the enthalpies of formation are between ?4.35 and ?3.22 kcal?mol^?1. The Cl halogen bonding between enflurane and water has been found in two complexes. The intermolecular (Cl···O) distance is smaller than the sum of the corresponding van der Waals radii. The CCSD(T)/CBS stabilization energies for these complexes are about ?2 kcal?mol^?1.

Density functional studies of the stepwise substitution of pyridine,pyridazine, pyrimidine,pyrazine, and 1,3,5-triazine with BCO

Ozone (O₃) adsorption on pristine Stone–Wales (SW) defective BC₃ graphene-like sheets was investigated using density functional calculations. It was found that O₃ is weakly adsorbed on the pristine sheet. Two types of SW-defective sheets were studied, SW-CC and SW-BC, in which a defect is formed by rotating a C–C or B–N bond, respectively. O₃ molecules were found to be more reactive on SW-BC defective sheets. It was predicted that O₃ molecules are reduced to O₂ molecules on SW-BC sheets, overcoming an energy barrier of 34.2 kcal/mol^?1 at the B3LYP level of theory and 27.2 kcal/mol^?1 at the BP98 level of theory. Therefore, SW-BC sheets could potentially be employed as a metal-free catalyst for O₃ reduction. The HOMO–LUMO gap of a SW-BC sheet decreases from 2.16 to 1.21 eV after O₃ dissociation on its surface in the most stable state.     

Phase-transition properties of glycerol-monopalmitate lipid bilayers investigated by molecular dynamics simulation: influence of the system size and force-field parameters

Phase-transition properties of glycerol-1-monopalmitate (GMP) bilayers are investigated using explicit-solvent molecular dynamics (MD) simulations, initiated from structures appropriate for the gel (GL) or liquid crystal (LC) phases, and carried out at different hydration levels and temperatures. Building up on a previous study and based on 600 ns simulations, the influence of the system size and of the force field on the equilibrium thermodynamic and dynamic parameters of the bilayers in the GL and LC phases, as well as on the temperature T_m and properties of the GL ? LC phase transition, are analysed. Qualitatively speaking, the results agree with the available experimental data for the area per lipid in the two phases and for the phase-transition temperatures at the three hydration levels irrespective of the selected model parameters. They also suggest that the total number of hydrogen bonds formed between a lipid headgroup and its environment is essentially constant, amounting to about four in both the LC and the GL phases. Quantitatively speaking, the dependence of T_m on the hydration level is found to be non-systematic across the different combinations of model parameters. This results in part from a sensitivity of the results on the system size and force-field parameters but also from the limited accuracy of the bracketing approach employed here to estimate T_m. Finally, a simple kinetic model is proposed to account for the timescales of the transitions. This model involves enthalpy and entropy increases of about 26 kJ mol^? 1 and 83 J mol^? 1 K^? 1 per lipid, upon going from the GL to the LC phase. The transition state is associated with activation parameters corresponding to 13% and 11%, respectively, of these values along the GL → LC transition, resulting in an activation free energy of about 0.3 kJ mol^? 1 per lipid at T_m.     

Zwitterionic conformers of pyrrolysine and their interactions with metal ions—a theoretical study

A total of 16 pyrrolysine conformers in their zwitterionic forms are studied in gas and simulated aqueous phase using a polarizable continuum model (PCM). These conformers are selected on the basis of our study on the intrinsic conformational properties of non-ionic pyrrolysine molecule in gas phase [Das and Mandal (2013) J Mol Model 19:1695?1704]. In aqueous phase, the stable zwitterionic pyrrolysine conformers are characterized by full geometry optimization and vibrational frequency calculations using B3LYP/6-311++G(d,p) level of theory. Single point calculations are also carried out at MP2/6-311++G(d,p) level. Characteristic intramolecular hydrogen bonds present in each conformer, their relative energies, theoretically predicted vibrational spectra, rotational constants and dipole moments are systematically reported. The calculated relative energy range of the conformers at B3LYP/6-311++G(d,p) level is 5.19 kcal mol^?1 whereas the same obtained by single point calculations at MP2/6-311++G(d,p) level is 4.58 kcal mol^?1. A thorough analysis reveals that four types of intramolecular H-bonds are present in the conformers; all of which play key roles in determining the energetics and in imparting the observed conformations to the conformers. The vibrational frequencies are found to shift invariably toward the lower side of frequency scale corresponding to the presence of the H-bonds. This study also points out that conformers with diverse structural motifs may differ in their thermodynamical stability by a narrow range of relative energy. The effects of metal coordination on the relative stability order and structural features of the conformers are examined by complexing five zwitterionic conformers of pyrrolysine with Cu⁺² through their carboxylate groups. The interaction enthalpies and Gibbs energies, rotational constants, vibrational frequencies and dipole moments of the metal complexes calculated at B3LYP level are also reported. The zwitterionic conformers of pyrrolysine are not stable in gas phase; after geometry optimization they are converted to the non-ionic forms.     

A study of the intermolecular association in living systems. IV. Studies on a model molecular fragment (pentane)

The low-lying energy states for the association of two molecules of n-pentane are determined by keeping one molecule fixed and rotating the second molecule simultaneously about its own x-, y-, and z- axes and also around the first molecule, all rotations being carried out from 0° to 360° in steps of 20° The interaction energy is calculated at each step, the form of the interaction energy used is the one given by Claverie &; Rein (1969). Results show that only a very limited number of orientations lead to energy states that are within 5 kcal mol^?1 of the minimum energy state.     

A theoretical investigation of the characteristics of hydrogen/halogen bonding interactions in dibromo-nitroaniline

In this work, computations of density functional theory (DFT) were carried out to investigate the nature of interactions in solid 2,6-dibromo-4-nitroaniline (DBNA). This system was selected to mimic the hydrogen/halogen bonding found within crystal structures as well as within biological molecules. DFT (M06-2X/6-311++G**) calculations indicated that the binding energies for different of interactions lie in the range between ?1.66 and ?9.77 kcal mol^?1. The quantum theory of atoms in molecules (QTAIM) was applied to provide more insight into the nature of these interactions. Symmetry-adapted perturbation theory (SAPT) analysis indicated that stability of the Br···Br halogen bonds is predicted to be attributable mainly to dispersion, while electrostatic forces, which have been widely believed to be responsible for these types of interactions, play a smaller role. Our results indicate that, for those nuclei participating in hydrogen/halogen bonding interactions, nuclear quadrupole resonance parameters exhibit considerable changes on going from the isolated molecule model to crystalline DBNA.

Theoretical study of the geometrical and electronic structures and thermochemistry of spherophanes

A set of supramolecular cage-structures—spherophanes—was studied at the density functional B3LYP level. Full geometrical structure optimisations were made with 6–31G and 6–31G(d) basis sets followed by frequency calculations, and electronic energies were evaluated at B3LYP/6–31++G(d,p). Three different symmetries were considered: C1, Ci, and Oh. It was found that the bonds between the benzene rings are very long to allow π-electron delocalisation between them. These spherophanes show portal openings of 2.596 Å in Spher1, 4.000 Å in Meth2, 3.659 Å in Oxa3, and 4.412 Å in Thia4. From the point of view of potential host–guest interaction studies, it should also be noted that the atoms nearest to the centre of the cavities are carbons bonded to X groups. These supramolecules seem to exhibit relatively large gap HOMO?LUMO: 2.89 eV(Spher1), 5.26 eV(Meth2), 5.73 eV(Oxa3), and 4.82 eV(Thia4). The calculated ΔH°_f (298.15 K) values at B3LYP/6–31G(d) are (in kcal mol^?1) 750.98, 229.78, ?10.97, and 482.49 for Spher1, Meth2, Oxa3, and Thia4, respectively. Using homodesmotic reactions, relative to Spher1, the spherophanes Meth2, Oxa3, and Thia4 are less strained by ?399.13 kcal mol^?1, ?390.40 kcal mol^?1, and ?411.38 kcal mol^?1, respectively. Their infrared and ¹³C NMR calculated spectra are reported.     

A theoretical investigation on the conformation and the interaction of CHF2OCF2CHF2 (desflurane II) with one water molecule

The conformation and the interaction of CHF₂OCF₂CHF₂ (desflurane II) with one water molecule is investigated theoretically using the ab initio MP2/aug-cc-pvdz and DFT-based M062X/6-311++G(d,p) methods. The calculations include the optimized geometries, the harmonic frequencies of relevant vibrational modes along with a natural bond orbital (NBO) analysis including the NBO charges, the hybridization of the C atom and the intra- and intermolecular hyperconjugation energies. In the two most stable conformers, the CH bond of the F₂HCO- group occupies the gauche position. The hyperconjugation energies are about the same for both conformers and the conformational preference depends on the interaction between the non-bonded F and H atoms. The deprotonation enthalpies of the CH bonds are about the same for both conformers, the proton affinity of the less stable conformer being 3 kcal mol^?1 higher. Both conformers of desflurane II interact with water forming cyclic complexes characterized by CH…O and OH…F hydrogen bonds. The binding energies are moderate, ranging from ?2.4 to ?3.2 kcal mol^?1 at the MP2 level. The origin of the blue shifts of the ν(CH) vibrations is analyzed. In three of the complexes, the water molecule acts as an electron donor. Interestingly, in these cases a charge transfer is also directed to the non bonded OH group of the water molecule. This effect seems to be a property of polyfluorinated ethers.     

Comparative density functional theory based study of the reactivity of Cu,Ag, and Au nanoparticles and of (111) surfaces toward CO oxidation and NO2 reduction

Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3β/CDK5 were calculated to be ?12.60?±?2.28 kcal mol^-1 and ?11.85?±?2.54 kcal mol^-1, respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3β/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3β/CDK5 and the valmerin-19 bound to GSK3β/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3β/CDK5 inhibitors.     

Quantum-chemical and empirical calculations on phospholipids. III. Hydration of the dimethylphosphate anion

The binding of water to the dimethylphosphate anion (DMP^?) was calculated using the PCILO method. We found binding energies of 25.95 kcal·mol^?1 in the O1-P-O3 plane bridging the anionic oxygen atoms and 19.3 kcal·mol^?1 for the one-site association of a water molecule to an anionic oxygen atom of DMP^?. In this range one water molecule added to DMP^? in the O1 … O3 bridged configuration has a significantly higher binding energy to DMP^? than water molecules added to other binding sites. The total binding energy of 5 water molecules to DMP^? is 92 kcal·mol^?1, a quantity which is about 10% less than the sum of the binding energies of the corresponding monohydrates.     

Nitrous oxide adsorption on pristine and Si-doped AlN nanotubes

Using density functional theory, we studied the adsorption of an N₂O molecule onto pristine and Si-doped AlN nanotubes in terms of energetic, geometric, and electronic properties. The N₂O is weakly adsorbed onto the pristine tube, releasing energies in the range of ?1.1 to ?5.7 kcal mol^-1. The electronic properties of the pristine tube are not influenced by the adsorption process. The N₂O molecule is predicted to strongly interact with the Si-doped tube in such a way that its oxygen atom diffuses into the tube wall, releasing an N₂ molecule. The energy of this reaction is calculated to be about ?103.6 kcal mol^-1, and the electronic properties of the Si-doped tube are slightly altered.     

Theoretical model of the aqua-copper [Cu(H2O)5]+cation interactions with guanine

Pentaaqua complexes of Cu(I) with guanine were optimized at the DFT B3PW91/6-31G(d) level. For the most stable structures, vibration frequencies and NBO charges were computed followed by energy analyses. The order of individual conformers was very sensitive to the method and basis sets used for the calculation. Several conformers are practically degenerated in energy. The inclusion of an entropy term changes the order of the conformers stability. Water molecules associated at the N9 position of guanine are favored by the inclusion of the entropy correction. Bonding energies of Cu–O(aqua) interactions were estimated to be about 60 kcal mol^–1 and for Cu–N7 bonding in the range of 75–83 kcal mol^–1. The broad range in Cu–N interaction energies demonstrates the role of induction effects caused by water molecules associated at the various sites of guanine. The charge distribution of the guanine molecule is changed remarkably by the coordination of a Cu(I) cation, which can also change the base-pairing pattern of the guanine.     

A large gap opening of graphene induced by the adsorption of CO on the Al-doped site

We investigated CO adsorption on the pristine, Stone-Wales (SW) defected, Al- and Si- doped graphenes by using density functional calculations in terms of geometric, energetic and electronic properties. It was found that CO molecule is weakly adsorbed on the pristine and SW defected graphenes and their electronic properties were slightly changed. The Al- and Si- doped graphenes show high reactivity toward CO, so calculated adoption energies are about ?11.40 and ?13.75 kcal mol^?1 in the most favorable states. It was found that, among all the structures, the electronic properties of Al-doped graphene are strongly sensitive to the presence of CO molecule. We demonstrate the existence of a large E_g opening of 0.87 eV in graphene which is induced by Al-doping and CO adsorption.     

Effect of stepwise microhydration on the methylammonium···phenol and ammonium···phenol interaction

A computational study has been performed for studying the characteristics of the interaction of phenol with ammonium and methylammonium cations. The effect of the presence of water molecules has also been considered by microhydrating the clusters with up to three water molecules. Clusters of phenol with ammonium and methylammonium cations present similar characteristics, though ammonium complexes have been found to be more stable than the methylammonium ones. The first water molecule included in the complexes interacts with a N-H group of ammoniun cations and simultaneously with the hydroxyl oxygen atom of phenol (or the aromatic ring). This first water molecule is more tightly bound in the complex, so the stability gain as more water molecules are included drops significantly by 2-3 kcal?mol^?1 with respect to the first one. As more water molecules are included, the differences between favorable coordination sites (the cation, the hydroxyl group or a previous water molecule) decrease. As a consequence, several of the most stable complexes located including three water molecules already exhibit hydrogen bonds between the hydroxyl group and one water molecule. The results indicate that a cyclic pattern formed by a series of hydrogen bonds: π···H-N-H···O-H···O-?, is characteristic of the most stable minima, being kept as more water molecules are included in the system. Therefore, this pattern can be expected to be crucial in ammonium cations···phenol interaction if exposed to the solvent to any degree.     

Density functional theory investigation of electrophilic addition reaction of bromine to tricyclo[4.2.2.22,5]dodeca-1,5-diene1

The geometry and the electronic structure of tricyclo[4.2.2.2^2,5]dodeca-1,5-diene (TCDD) molecule were investigated by DFT/B3LYP and /B3PW91 methods using the 6-311G(d,p) and 6-311++G(d,p) basis sets. The double bonds of TCDD molecule are syn-pyramidalized. The structure of π-orbitals and their mutual interactions for TCDD molecule were investigated. Potential energy surface (PES) of the TCDD-Br₂ system was studied by B3LYP/6-311++G(d,p) method and the configurations [molecular charge-transfer (CT) complex, transition states (TS1 and TS2), intermediate (INT) and product (P)] corresponding to the stationary points (minima or saddle points) were determined. Initially, a molecular CT-complex forms between Br₂ and TCDD. With a barrier of 22.336 kcal mol^-1 the CT-complex can be activated to an intermediate (INT) with energy 15.154 kcal mol^-1 higher than that of the CT-complex. The intermediate (INT) then transforms easily (barrier 5.442 kcal mol^-1) into the final, N-type product. The total bromination is slightly exothermic. Accompanying the breaking of Br-Br bond, C1-Br, C5-Br and C2-C6 bonds are formed, and C1 = C2 and C5 = C6 double bonds transform into single bonds. The direction of the reaction is determined by the direction of intramolecular skeletal rearrangement that is realized by the formation of C2-C6 bond.