Quantum mechanics/fluctuating charge calculations for absorption spectra of aqueous green fluorescent protein chromophore

We applied the quantum mechanics/fluctuating charges (QM/FQ) method to simulate the absorption spectra of three protonated forms of p-hydroxybenzylidene imidazolone (p-HBDI) in water. Configurations of solute-solvent were generated from molecular dynamics (MD) simulation within the context of a hybrid scheme in which solute and solvents were treated at QM and molecular mechanics, respectively. Nonperiodic spherical boundary condition was used. To examine the influence on simulated spectra coming from the geometrical relaxation of solute, the MD simulations were carried out for two cases: frozen and flexible molecular geometry of solute. As a result of our calculations, the simulations using the flexible solute's structure delivered vertical excitation energies closer to experimental data than those of a frozen solute, especially for the neutral case. For spectral broadening, changing from fixed geometry of solute to a flexible one led to a significant increase for both neutral and anionic forms of p-HBDI, but no effect happened for the cationic one.     

Study of the Alkaline Hydrolysis of the Azetidin-2-one Ring by ab initio Methods: Influence of the solvent

A comprehensive study of the alkaline hydrolysis of the β-lactam ring of azetidin-2-one was carried out using ab initio molecular-orbital calculations at the RHF/6-31 + G* level. The influence of the solvent on this reaction was investigated by using the reaction field method (SCRF); the solvent was found to suppress the interference of some gas-phase reactions and allow the presence of a transition state to be detected as the nucleophile approaches the β-lactam ring. The transition state corresponds to a structure where the OH^? group lies at a distance of 1.927 Å from the C?O group of the β-lactam ring and exhibits a potential barrier of 13.6 kcal/mol.     

Linear free‐energy relationships in chromium(VI) oxidation of substituted benzylamines in nonaqueous media

The kinetics of oxidation of 11 para‐ and meta‐substituted benzylamines by imidazolium fluorochromate (IFC) in different organic solvent media has been investigated in the presence of p‐toluenesulfonic acid (TsOH). The reaction was run under pseudo‐first‐order conditions. The rate of the reaction was found to be first order in IFC and found to increase with increase in [TsOH]. Solution IR studies in combination with kinetic measurements were used to get a better insight into the mechanism of the oxidation process. The product analysis was carried out using GC–MS. Various thermodynamic parameters for the oxidation have been reported and discussed along with the validity of the isokinetic relationship. The specific rate of oxidizing species benzylamines reaction (k₂) correlates with Hammett's substituent constants affording positive reaction constants. The rate data failed to correlate with macroscopic solvent parameters, such as ε_r and E^N_T, while showing satisfactory correlation with Kamlet–Taft's solvatochromic parameters (α, β, and π*) which suggests that the specific solute–solvent interactions play a major role in governing the reactivity, and the observed solvent effects have been explained on the basis of solute–solvent complexation. © 2007 Wiley Periodicals, Inc. Int J Chem Kinet 39: 362–369, 2007     

DFT and TD‐DFT investigation of IR and UV spectra of solvated molecules: Comparison of two SCRF continuum models

We report the calculation of liquid‐phase infrared (IR) and ultraviolet (UV) spectra in the framework of the solute's response to the reaction field of several solvents. In particular, we compare these two properties for the multipolar expansion model developed in the Nancy continuum model (NCM) and the polarized continuum model (PCM) scheme developed in Pise and Naples. All calculations are carried out at the (TD‐)DFT/6–311G(2d,2p) level of theory. The cavity size used for modeling the solute effects on the IR and UV spectra are examined. To calibrate the solute cavity size, we have investigated the IR spectra of coumarin and of a set of 14 additional solutes of different size and polarity in several dielectrical surroundings. It turns out that: (i) PCM and NCM present an identical behavior when a common cavity is used to calibrate the models; and (ii) for both NCM and PCM models, the IR spectra are highly sensitive to the solute and solvent polarity. The UV/VIS investigation of coumarin derivatives demonstrates that both models provide close estimates of λ_max independent of the solute cavity size. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Theoretical calculations of β-lactam antibiotics. V. AM1 calculations of hydrolysis of cephalothin in gaseous phase and influence of the solvent

A comprehensive study on the gas-phase alkaline hydrolysis of cephalosporins by using the semiempirical AM1 method was carried out. Cephalothin was the model compound used on account of the presence of a good leaving group at C(3′). According to the results obtained, the hydrolysis process takes place via a twostep reaction mechanism that involves the formation of an intermediate with a fully open β-lactam ring that still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the β-lactam carbonyl group of cephalosporins containing a good leaving group at C(3′). On the other hand, the alternative mechanism involving hydrolysis of the ester function in the side chain at 3′ and subsequent hydrolysis of the resulting β-lactam yieds essentially the corresponding enamine. The presence of a first solvation layer consisting of five water molecules showed that, even though some potential barriers are slightly increased, the mechanism involved is identical to that of the gas-phase hydrolysis of this antibiotic. © John Wiley & Sons, Inc.     

Theoretical study of ester enolate–imine condensation route to β-lactams

The condensation reaction of the enolate of methyl acetate with formaldimine to afford a β-lactam was studied using the MP2-FC/6-31+G* level of theory taking into account the electrostatic effect of the solvent by means of a self-consistent reaction field continuum model. The reaction is a stepwise process with three main steps: the formation of the C3(SINGLE BOND)C4 bond, the closure of the β-lactam ring, and the elimination of the methoxide ion. The formation of the C3(SINGLE BOND)C4 bond is rate determining and according to our calculations is not a reversible step. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1826–1833, 1998     

Molecular dynamics of cryptophane and its complexes with tetramethylammonium and neopentane using a continuum solvent model

Time scales currently obtainable in explicit–solvent molecular dynamics simulations are inadequate for the study of many biologically important processes. This has led to increased interest in the use of continuum solvent models. For such models to be used effectively, it is important that their behavior relative to explicit simulation be clearly understood. Accordingly, 5 ns stochastic dynamics simulations of a derivative of cryptophane-E alone, and complexed with tetramethylammonium and neopentane were carried out. Solvation electrostatics were accounted for via solutions to the Poisson equation. Nonelectrostatic aspects of solvation were incorporated using a surface area-dependent energy term. Comparison of the trajectories to those from previously reported 25 ns explicit–solvent simulations shows that use of a continuum solvent model results in enhanced sampling. Use of the continuum solvent model also results in a considerable increase in computational efficiency. The continuum solvent model is found to predict qualitative structural characteristics that are similar to those observed in explicit solvent. However, some differences are significant, and optimization of the continuum parameterization will be required for this method to become an efficient alternative to explicit–solvent simulation. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 956–970, 1999     

Solvents effects on the mechanism of cellulose hydrolysis: A QM/MM study

This article reports a combined quantum mechanics/molecular mechanics (QM/MM) investigation on the acid hydrolysis of cellulose in water using two different models, cellobiose and a 40‐unit cellulose chain. The explicitly treated solvent molecules strongly influence the conformations, intramolecular hydrogen bonds, and exoanomeric effects in these models. As these features are largely responsible for the barrier to cellulose hydrolysis, the present QM/MM results for the pathways and reaction intermediates in water are expected to be more realistic than those from a former density functional theory (DFT) study with implicit solvent (CPCM). However, in a qualitative sense, there is reasonable agreement between the DFT/CPCM and QM/MM predictions for the reaction mechanism. Differences arise mainly from specific solute–solvent hydrogen bonds that are only captured by QM/MM and not by DFT/CPCM. © 2015 Wiley Periodicals, Inc.     

Coupled semiempirical quantum mechanics and molecular mechanics (QM/MM) calculations on the aqueous solvation free energies of ionized molecules

The aqueous solvation free energies of ionized molecules were computed using a coupled quantum mechanical and molecular mechanical (QM/MM) model based on the AM1, MNDO, and PM3 semiempirical molecular orbital methods for the solute molecule and the TIP3P molecular mechanics model for liquid water. The present work is an extension of our model for neutral solutes where we assumed that the total free energy is the sum of components derived from the electrostatic/polarization terms in the Hamiltonian plus an empirical “nonpolar” term. The electrostatic/polarization contributions to the solvation free energies were computed using molecular dynamics (MD) simulation and thermodynamic integration techniques, while the nonpolar contributions were taken from the literature. The contribution to the electrostatic/polarization component of the free energy due to nonbonded interactions outside the cutoff radii used in the MD simulations was approximated by a Born solvation term. The experimental free energies were reproduced satisfactorily using variational parameters from the vdW terms as in the original model, in addition to a parameter from the one-electron integral terms. The new one-electron parameter was required to account for the short-range effects of overlapping atomic charge densities. The radial distribution functions obtained from the MD simulations showed the expected H-bonded structures between the ionized solute molecule and solvent molecules. We also obtained satisfactory results by neglecting both the empirical nonpolar term and the electronic polarization of the solute, i.e., by implementing a nonpolarization model. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1028–1038, 1999     

A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1

New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C–N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.     

Modeling solvent effects in molecular dynamics simulations of proteins

A series of computer simulations has been carried out on bovine pancreatic trypsin inhibitor using various models to mimic the effects of explicit bulk solvent on the structure of the protein. The solvent properties included are the polarization of the solute by the polar bulk solvent and the restraining effect on the motional freedom of the solute due to frictional drag at the solvent–protein surface interface. The former has been included by using a distance–dependent dielectric permittivity to screen the electrostatic interactions, whereas the latter is simulated by adding a limited number of solvent molecules near the protein surface. To achieve the proper mobility of the water molecules, their motion was restrained by adding a harmonic restraining force. It was found that a very small force constant was sufficient to model the static and dynamical behavior of the fully solvated solute, but that it was necessary to include enough explicit waters to occupy the first solvation shell. © 1992 John Wiley & Sons, Inc.     

Enantioselective Synthesis of β-Lactam Carried C(3) Functionality via Ester Enolate-Imine Condensation

Enantioselective synthesis of optically active β-lactam via ester enolate-imine condensation using homochiral ester 16 and imine 17 provided β-lactam 18a in 77% cc. Lactam 18a, carried C(3) functionality on β-lactam nuclei, provided a potential precursor toward a synthesis of dipeptide antibiotic.     

Molecular surfaces: An advantageous starting point for the description of composition‐dependent viscosities applied to polymer solutions

The viscosity of polymer/solvent systems is modeled as a function of composition under the premises that the dissipation of energy is taking place at the molecular interfaces and that the friction between solvent and solute varies with composition due to a change in the flow mechanism (drainage of coils). The simple expression obtained in this manner contains three system‐specific parameters: a geometric factor γ, which accounts for the differences of the surface to volume ratios of the components; a hydrodynamic parameter α, which measures the friction between solute and solvent in the case of fully draining polymer coils; and β, which corrects for changes in the friction between unlike molecules resulting from collective motions owing to limited draining. Experimental data published for 12 poly(dimethylsiloxane)/pentamer mixtures can be represented quantitatively by this relation; moreover the knowledge of the three system‐specific parameters permits the calculation of intrinsic viscosities, and the molecular weight dependencies of γ and α yield the entangle molecular weight of the polymer. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 2221–2228, 1999     

Use of Masson's and Jones–Dole equations to study different types of interactions of three pharmacologically important drugs in ethanol

The volumetric and viscometric study of three allopathic drugs (sodium valporate, benzalkonium chloride, and losartan potassium) in ethanol solvent is reported here. This study was carried out at four different temperatures that is, from 288.15 to 318.15 K. The accurately measured density values were used to calculate partial molar volume at infinite dilution, solute–solute interaction parameter, Hepler's constant, partial molar expansivity constant, and isobaric thermal expansion coefficient. The viscosity measurements were carried out for the calculation of constants of Jones–Dole equation and to calculate different thermodynamic parameters of viscous flow which include standard free energy change, standard enthalpy change, and standard entropy change of viscous flow. All these viscometric and volumetric parameters are useful for understanding the different types of interactions of drugs in solution and to study the drug action in body. The results of both volumetric and viscometric studies showed that all drugs had structure promoting effect on solvent, existing of strong solute–solvent interaction, and very weak solute–solute interaction. For all these drugs, solvophobic interaction was found to be dominant over electrostriction. Viscometric studies also showed the existing of stronger solute–solvent interaction in ground state as compared to that in transition state.     

Influence of the solvent representation on vibrational entropy calculations: Generalized born versus distance‐dependent dielectric model

The harmonic model is the most popular approximation for estimating the “configurational” entropy of a solute in molecular mechanics/Poisson‐Boltzmann solvent accessible surface area (MM/PBSA)‐type binding free energy calculations. Here, we investigate the influence of the solvent representation in the harmonic model by comparing estimates of changes in the vibrational entropies for 30 trypsin/ligand complexes on ligand binding. Second derivatives of Amber generalized Born (GB) solvation models are available in the nucleic acid builder code. They allow one to use these models for the calculation of vibrational entropies instead of using a simpler solvation model based on a distance‐dependent dielectric (DDD) constant. Estimates of changes in the vibrational entropies obtained with a DDD model are systematically and significantly larger, by on average, 6 kcal mol^?1 (at T = 300 K), than estimates obtained with a GB model and so are more favorable for complex formation. The difference becomes larger the more the vibrational entropy contribution disfavors complex formation, that is, the larger the ligand is (for the complexes considered here). A structural decomposition of the estimates into per‐residue contributions reveals polar interactions between the ligand and the surrounding protein, in particular involving charged nitrogens, as a main source of the differences. Snapshots minimized with the DDD model showed a structural deviation from snapshots minimized in explicit water that is larger by, on average, 0.5 Å RMSD compared to snapshots that were minimized with GB^HCT. As experimental vibrational entropies of biomacromolecules are elusive, there is no direct way to establish a solvent model's superiority. Thus, we can only recommend using the GB harmonic model for vibrational entropy calculations based on the reasoning that smaller structural deviations should point to the implicit solvent model that closer approximates the energy landscape of the solute in explicit solvent. © 2012 Wiley Periodicals, Inc.     

A new set of atomic radii for accurate estimation of solvation free energy by Poisson–Boltzmann solvent model

The Poisson–Boltzmann implicit solvent (PB) is widely used to estimate the solvation free energies of biomolecules in molecular simulations. An optimized set of atomic radii (PB radii) is an important parameter for PB calculations, which determines the distribution of dielectric constants around the solute. We here present new PB radii for the AMBER protein force field to accurately reproduce the solvation free energies obtained from explicit solvent simulations. The presented PB radii were optimized using results from explicit solvent simulations of the large systems. In addition, we discriminated PB radii for N‐ and C‐terminal residues from those for nonterminal residues. The performances using our PB radii showed high accuracy for the estimation of solvation free energies at the level of the molecular fragment. The obtained PB radii are effective for the detailed analysis of the solvation effects of biomolecules. © 2014 The Authors Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Incorporating the excluded solvent volume and surface charges for computing solvation free energy

Gauss's law or Poisson's equation is conventionally used to calculate solvation free energy. However, the near‐solute dielectric polarization from Gauss's law or Poisson's equation differs from that obtained from molecular dynamics (MD) simulations. To mimic the near‐solute dielectric polarization from MD simulations, the first‐shell water was treated as two layers of surface charges, the densities of which are proportional to the electric field at the solvent molecule that is modeled as a hard sphere. The intermediate water was treated as a bulk solvent. An equation describing the solvation free energy of ions using this solvent scheme was derived using the TIP3P water model. © 2013 Wiley Periodicals, Inc.     

Theoretical Calculations of β-Lactam Antibiotics. Part VII. Influence of the solvent on the basic hydrolysis of the β-lactam ring

We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OH^? ion on the β-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OH^? ion in approaching the β-lactam carbonyl group. Using the supermolecular approach and a H₂O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).