Conformational Energy Differences Research Articles

Excited state dynamics of a double ESIPT unit comprising fluorophore

A comprehensive experimental and computational analysis on the photophysical characteristics of a double ESIPT unit based fluorescent molecule, 2,2′-(1,4-phenylenebis(1H-benzo[d]imidazole-1,2-diyl))diphenol (PBIDP), was carried out. Photoluminescence spectra and lifetime decays have been measured in various polar and nonpolar solvents to explore the fluorescence properties. Furthermore, time-resolved area normalized emission spectra are exploited to identify the different conformers to the unsymmetrical keto emission band correlating with their lifetime values. To corroborate the experimental observations, computations have been enacted by calculating the relative energy, excitation and emission energies of different conformers. Especially, the simulation facilitates to trace the reason behind the triple emissions, uncovering the proton transfer dynamics in the double ESIPT based PBIDP system. Additionally, to understand the ESIPT mechanism in the fluorophore, the potential energy curve and transition state in the ground, and excited state were calculated.

DFT Calculation for Newly Synthesized 2-Chloro-1-(3-methyl-3-mesityl-cyclobutyl)– ethanone

The synthesis of cyclobutane rings, particularly stereospecifically, poses significant challenges in synthetic chemistry due to the highly strained ring topologies. The cyclobutane-containing natural products are appealing targets for total synthesis due to their new chemical structures and exceptional biological activity. In this study, we have presented the synthesis and structure analysis of 2-chloro-1-(3-methyl-3-mesityl-cyclobutyl)–ethanone. The molecular elucidation was conducted by Fourier transform infrared (IR) and Nuclear magnetic spectroscopy (NMR). The I recording in 4000-500cm-1 was done in the potassium bromide solid phase, while the NMR for both Hydrogen and Carbon was done in the Dimethyl sulfoxide-6. Density functional theory (DFT) was used to stimulate and confirm the structure and molecular characterization. Using DFT/cc-pVDZ method to study various conformers of the compound and their minimum energies by the scanning potential energy surface. In addition, the molecular electrostatic potential map (MEP) and charge spreading have been plotted for the molecule to account for the chemical reactivity and site selectivity. Furthermore, the thermodynamic properties of the molecule have been studied. A good correlation was found between experimental and stimulation studies for Fourier transform infrared and Nuclear magnetic spectroscopy results. In the stimulation data, the conformer's energy differences were very small.

Dissecting Solvent Effects on Hydrogen Bonding

AbstractThe experimental isolation of H‐bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H‐bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H‐bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas‐phase computed energies exhibited wild solvent‐dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/β solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H‐bonds.

Dissecting Solvent Effects on Hydrogen Bonding.

The experimental isolation of H‐bond energetics from the typically dominant influence of the solvent remains challenging. Here we use synthetic molecular balances to quantify amine/amide H‐bonds in competitive solvents. Over 200 conformational free energy differences were determined using 24 H‐bonding balances in 9 solvents spanning a wide polarity range. The correlations between experimental interaction energies and gas‐phase computed energies exhibited wild solvent‐dependent variation. However, excellent correlations were found between the same computed energies and the experimental data following empirical dissection of solvent effects using Hunter's α/β solvation model. In addition to facilitating the direct comparison of experimental and computational data, changes in the fitted donor and acceptor constants reveal the energetics of secondary local interactions such as competing H‐bonds.

Conformational Change in Molecular Crystals: Impact of Solvate Formation and Importance of Conformational Free Energies

Changes in molecular conformation and its relationship with crystal polymorphism have been well documented in previous work. To the best of our knowledge, however, the effect of solvate formation on molecular conformation has never been explored. Using the Cambridge Structural Database in combination with molecular modeling, we provide insights into the impact of solvate formation on the conformation adopted by a compound and whether such conformation is different to that found in its neat form(s). Typically, the more flexible a molecule is, the higher the chances that conformational change occurs upon solvate formation. There are no trends as to the relative stability of conformers and their likelihood to be observed in either the solvates or the neat forms. Typically, conformer energy differences in solvate-neat form pairs are small (<5 kJ/mol) and when larger energy differences are observed (>15 kJ/mol), these can be reduced significantly when both solvent and thermal effects are considered in the simulations. This highlights of the importance of computing thermal contributions in conformer energies as well as accounting for environmental effects. Overall, we find that conformational change in solvate-neat form pairs mirrors the behavior of conformational change in polymorphism.

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

PurposeApplication of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing.MethodsMolecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields.ResultsThe form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability.ConclusionInter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

Benchmark comparison of dual-basis double-hybrid density functional theory and a neural-network-optimized method for intermolecular interactions

We present a computationally efficient implementation of double-hybrid density functional theory (DH-DFT) leveraging the dual basis methods of Head-Gordon and co-workers and the resolution-of-the-identity second-order Møller-Plesset (RI-MP2) theory. The B2PLYP, B2GP-PLYP, DSD-BLYP and DSD-PBEP86 density functionals are applied to assess the performance of dual-basis methods on several benchmark test cases, including the CONF set of conformational energy differences in C4-C7 alkanes, the S22 set of noncovalent interaction energies, and the RGC10 noble-gas dimer dissociation curves. The dual-basis DH-DFT approach is shown to give results in excellent agreement with conventional methods at a reduced computational cost. For noncovalent interaction energies, DH-DFT is compared against a leading neural-network-based approach, namely the SNS-MP2 method of McGibbon and coworkers (McGibbon et al., 2017). The DH-DFT and SNS-MP2 methods are shown to produce similar accuracies when compared to the established benchmark values.

Excited States Calculation of Some Alkyl Sulfides with Time-Dependent Density Functional Theory

The excited states of mustard and related alkyl sulfides have been calculated using time-dependent density functional theory. Among the seven commonly used density functionals, PBE0 exhibits the most accurate excited energy, while the Pearson-related coefficient of calculated energies and experimental peaks reaches 0.98. Boltzmann average analysis reveals that excited energies of different conformers are almost the same. The calculated excited states of mustard come to 5.56 and 6.00 eV, which are assigned as n → σ* transition by the natural transition orbital visualization. Besides, sulfur ethers with C2ν symmetry show similar ultraviolet properties as mustard, whereas the excited states of simulated agents with the SCH2CH2Cl group differ from mustard.

Theoretical and Experimental Investigations of Spectroscopic Properties of 2-Thiophenecarbonyl chloride

Molecular structure and vibrational wave numbers for 2-Thiophenecarbonyl chloride have been computed using the B3LYP method with the 6-311++G (d, p) basis set. The computation reveals that the title compound has two minimal conformers (gauche and syn). The conformational energy difference between the syn and gauche is very small, indicating that the syn conformer coexists with the gauche conformer. FT-IR and FT-Raman spectra of 2-Thiophenecarbonyl chloride were recorded and analysed in the range 3500-400 and 3500-200cm-1, respectively. The HOMO-LUMO energy gap of the two conformers have been also calculated for comparison of their chemical activities.

Structures and conformational dynamics of trans- and cis-crotonaldehydes in excited electronic states: A quantum-chemical study

For trans- and cis-crotonaldehydes CH3CHCHCHO in the triplet and singlet lowest excited electronic states of n,π* and π,π* types, the geometries of conformers, conformer energy differences, and conformational dynamics have been addressed using ab initio multi-reference techniques (CASSCF and CASPT2). The conformers of investigated molecules under study have been shown to possess a symmetry plane in 1,3(n,π*) states and to be significantly non-planar in 1,3(π,π*) states. Couplings of asymmetric internal rotations around CC and CC bonds with others large amplitude molecular motions such as methyl torsion, non-planar distortions of CCHO, CCHC, and CCH(CH3) fragments are discussed. The type of coupling between large-amplitude motions has been shown to be connected with the localization of electronic excitation.

The Polymorphs of ROY: A Computational Study of Lattice Energies and Conformational Energy Differences

The remarkable structural diversity observed in polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (commonly known as ROY) challenges computational attempts to predict or rationalize their relative stability. This modest study explores the applicability of CE-B3LYP model energy calculation of lattice energies (using experimental crystal structures), supplemented by a systematic approach to account for conformational energy differences. The CE-B3LYP model provides sensible estimates of absolute and relative lattice energies for the polymorphs, provided care is taken to achieve convergence in the summation of pairwise terms. Conformational energy differences based on density functional theory (DFT) energies are shown to be unreliable, but MP2 energies based on DFT-optimized structures show considerable promise.

Computation of Hemagglutinin Free Energy Difference by the Confinement Method.

Hemagglutinin (HA) mediates membrane fusion, a crucial step during influenza virus cell entry. How many HAs are needed for this process is still subject to debate. To aid in this discussion, the confinement free energy method was used to calculate the conformational free energy difference between the extended intermediate and postfusion state of HA. Special care was taken to comply with the general guidelines for free energy calculations, thereby obtaining convergence and demonstrating reliability of the results. The energy that one HA trimer contributes to fusion was found to be 34.2 ± 3.4kBT, similar to the known contributions from other fusion proteins. Although computationally expensive, the technique used is a promising tool for the further energetic characterization of fusion protein mechanisms. Knowledge of the energetic contributions per protein, and of conserved residues that are crucial for fusion, aids in the development of fusion inhibitors for antiviral drugs.

Calculation of conformational free energies by confinement simulations in explicit water with implicit desolvation

The confinement method is a robust and conceptually simple free energy simulation method that allows the calculation of conformational free energy differences between highly dissimilar states. Application of the method to explicitly solvated systems requires a multi-stage simulation protocol for the calculation of desolvation free energies. Here we show that these desolvation free energies can be readily obtained from an implicit treatment, which is simpler and less costly. The accuracy and robustness of this protocol was shown by the calculation of conformational free energy differences of a series of explicitly solvated test systems. Given the accuracy and ease by which these free energy differences were obtained, the confinement method is promising for the treatment of conformational changes in large and complex systems.

Conformational analysis of N-methylacetamide molecule in the ground and excited electronic states

Equilibrium geometry parameters, harmonic vibrational frequencies and barriers to conformational transitions and conformer energy differences for N-methylacetamide (CH3CONHCH3) molecule in S0, S1 and T1 electronic states were calculated in MP2 (S0) and CASPT2 (S1, T1) levels of theory. It is known that there are two planar (or effectively planar) conformers of N-methylacetamide in the ground electronic state. It is proved that the electronic excitation to aforementioned electronic states resulted in both CCON and HNCC fragments becoming pyramidal and rotated around «central» CN bond. One-, two- and three-dimensional potential energy surface (PES) sections by different large amplitude motions (LAM) coordinates were obtained by MP2 (S0) and CASPT2 (S1, T1) methods with cc-pVTZ basis set. On 2D PES sections by «central» torsion (CN) and one of the CCON or HNCC fragments’ inversion coordinates there are six different minima. Using PES sections as the potentials in model Hamiltonians, different anharmonic vibrational problems were solved and the frequencies of large amplitude vibrations were estimated variationally.

Augmenting the anisotropic network model with torsional potentials improves PATH performance, enabling detailed comparison with experimental rate data.

PATH algorithms for identifying conformational transition states provide computational parameters—time to the transition state, conformational free energy differences, and transition state activation energies—for comparison to experimental data and can be carried out sufficiently rapidly to use in the “high throughput” mode. These advantages are especially useful for interpreting results from combinatorial mutagenesis experiments. This report updates the previously published algorithm with enhancements that improve correlations between PATH convergence parameters derived from virtual variant structures generated by RosettaBackrub and previously published kinetic data for a complete, four-way combinatorial mutagenesis of a conformational switch in Tryptophanyl-tRNA synthetase.

Conformational analysis of acetamide in the ground and lowest excited electronic states

For acetamide molecule (CH3CONH2) in the ground (S0) and lowest excited singlet (S1) and triplet (T1) electronic states calculations of equilibrium geometry parameters, harmonic vibrational frequencies and barriers to conformational transitions (also conformer energy differences in excited states) using following ab initio methods: MP2, CCSD(T), CASSCF, CASPT2 and MRCI were performed. One-, two- and three-dimensional potential energy surface (PES) sections by different large amplitude motions (LAM) coordinates were calculated by means of MP2/aug-cc-pVTZ (S0) and CASPT2/cc-pVTZ (S1, T1). As a result of electronic excitation, both CCON and CNH2 fragments become pyramidal. On 2D PES sections by torsion (CN) and inversion coordinates there are six minima forming three pairs of enantiomers. Using PES sections different anharmonic vibrational problems were solved and the frequencies of large amplitude vibrations were estimated.

Computing conformational free energy differences in explicit solvent: An efficient thermodynamic cycle using an auxiliary potential and a free energy functional constructed from the end points.

Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: (1) The conformational free energy changes for alanine dipeptide transitioning from the right-handed free energy basin to the left-handed basin and (2) the free energy difference between the open and closed conformations of β-cyclodextrin, a "host" molecule that serves as a model for molecular recognition in host-guest binding. β-cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, making β-cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with two endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for the β-cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required. © 2016 Wiley Periodicals, Inc.

On large amplitude motions of simplest amides in the ground and excited electronic states

For the formamide, acetamide, N-methylformamide and N-methylacetamide molecules in the ground (S0 ) and lowest excited singlet (S1 ) and triplet (T1 ) electronic states equilibrium geometry parameters, harmonic vibrational frequencies, barriers to conformational transitions and conformer energy differences were estimated by means of MP2, CCSD(T), CASSCF, CASPT2 and MRCI ab initio methods. One-, two- and three-dimensional potential energy surface (PES) sections corresponding to different large amplitude motions (LAM) were calculated by means of MP2/aug-cc-pVTZ (S0 ) and CASPT2/cc-pVTZ (S1 ,T1 ). For these molecules, in each excited electronic state six minima were found on 2D PES sections. Using PES sections, different anharmonic vibrational problems were solved and the frequencies of large amplitude vibrations were determined.

Complexes of a Zn-metalloenzyme binding site with hydroxamate-containing ligands. A case for detailed benchmarkings of polarizable molecular mechanics/dynamics potentials when the experimental binding structure is unknown.

Zn-metalloproteins are a major class of targets for drug design. They constitute a demanding testing ground for polarizable molecular mechanics/dynamics aimed at extending the realm of quantum chemistry (QC) to very long-duration molecular dynamics (MD). The reliability of such procedures needs to be demonstrated upon comparing the relative stabilities of competing candidate complexes of inhibitors with the recognition site stabilized in the course of MD. This could be necessary when no information is available regarding the experimental structure of the inhibitor-protein complex. Thus, this study bears on the phosphomannose isomerase (PMI) enzyme, considered as a potential therapeutic target for the treatment of several bacterial and parasitic diseases. We consider its complexes with 5-phospho-d-arabinonohydroxamate and three analog ligands differing by the number and location of their hydroxyl groups. We evaluate the energy accuracy expectable from a polarizable molecular mechanics procedure, SIBFA. This is done by comparisons with ab initio quantum-chemistry (QC) calculations in the following cases: (a) the complexes of the four ligands in three distinct structures extracted from the entire PMI-ligand energy-minimized structures, and totaling up to 264 atoms; (b) the solvation energies of several energy-minimized complexes of each ligand with a shell of 64 water molecules; (c) the conformational energy differences of each ligand in different conformations characterized in the course of energy-minimizations; and (d) the continuum solvation energies of the ligands in different conformations. The agreements with the QC results appear convincing. On these bases, we discuss the prospects of applying the procedure to ligand-macromolecule recognition problems. © 2016 Wiley Periodicals, Inc.

Mechanisms of chain adsorption on porous substrates and critical conditions of polymer chromatography

Polymer adsorption is a ubiquitous phenomenon with numerous technological and healthcare applications. The mechanisms of polymer adsorption on surfaces and in pores are complex owing to a competition between various entropic and enthalpic factors. Due to adsorption of monomers to the surface, the chain gains in enthalpy yet loses in entropy because of confining effects. This competition leads to the existence of critical conditions of adsorption when enthalpy gain and entropy loss are in balance. The critical conditions are controlled by the confining geometry and effective adsorption energy, which depends on the solvent composition and temperature. This phenomenon has important implications in polymer chromatography, since the retention at the critical point of adsorption (CPA) is chain length independent. However, the mechanisms of polymer adsorption in pores are poorly understood and there is an ongoing discussion in the theoretical literature about the very existence of CPA for polymer adsorption on porous substrates.In this work, we examine the mechanisms of chain adsorption on a model porous substrate using Monte Carlo (MC) simulations. We distinguish three adsorption mechanisms depending on the chain location: on external surface, completely confined in pores, and also partially confined in pores in so-called “flower” conformations. The free energies of different conformations of adsorbed chains are calculated by the incremental gauge cell MC method that allows one to determine the partition coefficient as a function of the adsorption potential, pore size, and chain length. We confirm the existence of the CPA for chain length independent separation on porous substrates, which is explained by the dominant contributions of the chain adsorption at the external surface, in particular in flower conformations. Moreover, we show that the critical conditions for porous and nonporous substrates are identical and depend only on the surface chemistry. The theoretical results are confirmed by comparison with experimental data on chromatographic separation of a series of linear polystyrenes.