Drug resistant Mycobacterium tuberculosis, which mostly results from single nucleotide polymorphisms in antibiotic target genes, poses a major threat to tuberculosis treatment outcomes. Relative binding free energy (RBFE) calculations can rapidly predict the effects of mutations, but this approach has not been tested on large, complex proteins. We use RBFE calculations to predict the effects of M. tuberculosis RNA polymerase and DNA gyrase mutations on rifampicin and moxifloxacin susceptibility respectively. These mutations encompass a range of amino acid substitutions with known effects and include large steric perturbations and charged moieties. We find that moderate numbers (n = 3-15) of short RBFE calculations can predict resistance in cases where the mutation results in a large change in the binding free energy. We show that the method lacks discrimination in cases with either a small change in energy or that involve charged amino acids, and we investigate how these calculation errors may be decreased.

In this work, various precious and non-precious metals reported in the literature as the most effective catalysts for glucose electrooxidation reaction were investigated by the density functional theory (DFT) approach in order to reveal the mechanisms taking place over the catalysts in the fuel cell. The use of a single-atom catalyst model was adopted by insertion of one Au, Cu, Ni, Pd, Pt, and Zn metal atom on the pyridinic N atoms doped graphene surface (NG). β form of d-glucose in alkaline solution was used to determine the reaction mechanism and intermediates that formed during the reaction. DFT results showed that the desired glucono-lactone was formed on the Cu-3NG electrode in a single-step reaction pathway whereas it was produced via different two-step pathways on the Au and Pt-3NG electrodes. Although the interaction of glucose with Ni, Pd, and Zn-doped surfaces resulted in the deprotonation of the molecule, lactone product formation did not occur on these electrode surfaces. When the calculation results are evaluated in terms of energy content and product formation, it can be concluded that Cu, Pt, and especially Au doped graphene catalysts are effective for direct glucose oxidation in fuel cells reactor.

Quantum chemical calculations have been carried out to investigate the hydrogen storage capacity of Be2 (NLi)2 cluster. Calculations reveal that the cluster can take up to eight H2 molecules reaching a maximum gravimetric density of 21.04 wt%. Six H2 molecules bind at the Li atoms and two H2 bind at the Be atoms with moderate binding energy which is required for reversible storage of H2 . Symmetry-adapted perturbation analysis reveals the significant contribution of electrostatic and induction and very minor contribution of dispersion toward the total interaction energy. Molecular dynamics simulations reveal that the H2 molecules are strongly bound at 77 K and get slowly released at elevated temperatures.

Atoms in molecules, noncovalent index, and natural bond orbital methods are commonly invoked to identify the presence of various noncovalent bonds and to measure their strength. However, there are numerous instances in the literature where these methods provide contradictory or apparently erroneous interpretations of the bonding. The range of reliability of these methods is assessed by calculations of a variety of systems, which include an H-bond, halogen bond, π-tetrel bond, CH··HC interaction, and a pairing of two anions. While the results appear to be meaningful for the equilibrium geometries, and those where the two subunits are progressively pulled apart, these techniques erroneously predict a progressively stronger bonding interaction as the two units are compressed and the interaction becomes clearly repulsive. The methods falsely indicate a bonding interaction in the CH··HC arrangement, and incorrectly mimic the behavior of the energy when two anions approach. These approaches are also unreliable for understanding angular deformations.

Computing the free energies of molecular mechanisms in multidimensional space relies on combinations of geometrically complex reaction coordinates. We show how a graph theory implementation reduces complexity, and illustrate this on the arrangements of hydrogen bonding of a water dimer. The reaction coordinates and forces are computed using graphs that define the dependencies on the atoms in the Free Energy from Adaptive Reaction Coordinate Forces (FEARCF) library. The library can be interfaced with classical molecular dynamics as well as quantum molecular dynamics packages. Multidimensional interdependent reaction coordinates are constructed to produce complex free energy hypersurfaces. The reaction coordinates are graphed from atomic and molecular components to define points, distances, vectors, angles, planes and combinations thereof. The resultant free energy surfaces that are a function of the distance, angles, planes, and so on, can represent molecular mechanisms in reduced dimensions from the component atomic Cartesian coordinate degrees of freedom. The FEARCF library can be interfaced with any molecular package. Here, we demonstrate the link to NWChem to compute a hyperdimensional DFT (aug-cc-pVDZ basis set and X3LYP exchange correlation functionals) free energy space of a water dimer. Analysis of the water dimer free energy hypervolume reveals that while the chain and cyclic hydrogen bonding configurations are located in stable minimum energy wells, the bifurcated hydrogen bond configuration is a gateway to instability and dimer dissociation.

The trapping reactions of carbene analogs G14F2 (G14 = group 14 element) by the benzene-bridged B/P-Rea frustrated Lewis pair (FLPs) molecule are studied using density functional theory (B3LYP-D3(BJ)/def2-TZVP). Our theoretical investigations predict that only the CF2 intermediate rather than other heavy carbene analogs can be trapped by the B/P-Rea FLP-type molecule. Energy decomposition analysis-natural orbitals for chemical valence (EDA-NOCV) analyses indicate that the bonding nature of the G14F2 catching reactions by the B/P-Rea FLP-type molecule is a donor-acceptor (singlet-singlet) interaction rather than an electron-sharing (triplet-triplet) interaction. Moreover, EDA-NOCV and frontier molecular orbital (FMO) theory findings strongly suggest that the lone pair (LP) (P) → vacant p-π-orbital (G14F2 ) interaction rather than the empty σ-orbital (B) ← sp2 -σ-orbital (G14F2 ) interaction plays a predominant role in establishing its bonding condition during the G14F2 trapping reaction with the B/P-Rea FLP-associated molecule. Our activation strain model findings reveal that the atomic radius of the G14 element of G14F2 plays a key role in determining the activation barrier of the G14F2 trapping reactions by the benzene-bridged B/P-Rea FLP. The valence bond state correlation diagram (VBSCD) model developed by Shaik is used to rationalize the calculated results. The VBSCD findings demonstrate that in the present trapping reactions, the singlet triplet splitting of G14F2 plays a significant role in influencing its reaction barrier and reaction enthalpy. Our theoretical results demonstrate that the relationship between the geometrical parameters of the transition states and the corresponding reaction free energy barriers agrees well with the findings based on the Hammond postulate.

Molecular self-diffusion coefficients underlie various kinetic properties of the liquids involved in chemistry, physics, and pharmaceutics. In this study, 547 self-diffusion coefficients are calculated based on all-atom molecular dynamics (MD) simulations of 152 diverse pure liquids at various temperatures employing the OPLS4 force field. The calculated coefficients are compared with experimental data (424 extracted from the literature and 123 newly measured by pulsed-field gradient nuclear magnetic resonance). The calculations well agree with the experimental values. The determination coefficient and root mean square error between the observed and calculated logarithmic self-diffusion coefficients of the 547 entries are 0.931 and 0.213, respectively, demonstrating that the MD calculation can be an excellent industrial tool for predicting, for example, molecular transportation in liquids such as the diffusion of active ingredients in biological and pharmaceutical liquids. The self-diffusion coefficients collected in this study are compiled into a database for broad researches including artificial intelligence calculations.

A new set of auxiliary basis function suitable to fit the induced electron density is presented. Such set has been optimized in order to furnish accurate absorption spectra using the complex polarizability algorithm of time-dependent density functional theory (TDDFT). An automatic procedure has been set up, able, thanks to the definition of suitable descriptors, to evaluate the resemblance of the auxiliary basis-dependent calculated spectra with respect to a reference. In this way, it has been possible to reduce the size of the basis set maximizing the basis set accuracy. Thanks to the choice to employ a collection of molecules for each element, such basis has proven transferable to molecules outside the collection. The final sets are therefore much more accurate and smaller than the previously optimized ones and have been already included in the database of the last release of the AMS suite of programs. The availability of the present new set will allow to improve drastically the applicability range of the polTDDFT method with higher accuracy and less computational effort.

Two new relativistic adapted Gaussian basis sets of small and medium size are presented for all elements from Hydrogen through Xenon. These sets are free of variational prolapse and were developed with the polynomial generator coordinate Dirac-Fock method to be used with two finite nuclear models, uniform sphere and Gaussian. The largest basis set errors for electronic configurations from the Aufbau principle are around 10.0 and 4.7 mHartree for the small- and medium-size sets, respectively, which is in accordance with the accuracy level expected in each case. Hence, to our knowledge, these are the smallest prolapse free basis sets developed for these elements.

Early-stage drug discovery projects often focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. The kinetics of drug binding are ignored but can have significant influence on drug efficacy. Therefore, increasing attention has been paid on evaluating drug-binding kinetics early in a drug discovery process. Simulating drug-binding kinetics at the atomic level is challenging for the long time scale involved. Here, we used the transition-based reweighting analysis method (TRAM) with the Markov state model to study the dissociation of a ligand from the protein kinase PYK2. TRAM combines biased and unbiased simulations to reduce computational costs. This work used the umbrella sampling technique for the biased simulations. Although using the potential of mean force from umbrella sampling simulations with the transition-state theory over-estimated the dissociation rate by three orders of magnitude, TRAM gave a dissociation rate within an order of magnitude of the experimental value.

Conformer-RL is an open-source Python package for applying deep reinforcement learning (RL) to the task of generating a diverse set of low-energy conformations for a single molecule. The library features a simple interface to train a deep RL conformer generation model on any covalently bonded molecule or polymer, including most drug-like molecules. Under the hood, it implements state-of-the-art RL algorithms and graph neural network architectures tuned specifically for molecular structures. Conformer-RL is also a platform for researching new algorithms and neural network architectures for conformer generation, as the library contains modular class interfaces for RL environments and agents, allowing users to easily swap components with their own implementations. Additionally, it comes with tools to visualize and save generated conformers for further analysis. Conformer-RL is well-tested and thoroughly documented with tutorials for each of the functionalities mentioned above, and is available on PyPi and Github: https://github.com/ZimmermanGroup/conformer-rl.

An approximate approach to quantum vibrational dynamics, "Brownian chain molecular dynamics (BCMD)," is proposed to alleviate the chain resonance and curvature problems in the imaginary time-based path integral (PI) simulation. Here the non-centroid velocity is randomized at each step when solving the equation of motion of path integral molecular dynamics. This leads to a combination of the Newton equation and the overdamped Langevin equation for the centroid and non-centroid variables, respectively. BCMD shares the basic properties of other PI approaches such as centroid and ring polymer molecular dynamics: It gives the correct Kubo-transformed correlation function at short times, conserves the time symmetry, has the correct high-temperature/classical limits, gives exactly the position and velocity autocorrelations of harmonic oscillator systems, and does not have the zero-point leakage problem. Numerical tests were done on simple molecular models and liquid water. On-the-fly ab initio BCMD simulations were performed for the protonated water cluster, H5O2+ , and its isotopologue, D5O2+ .

Performance of contemporary tight-binding semiempirical GFNn-xTB methods for the conformational energies of singly charged sodium clusters Na+ (S)n (n = 4-8) with 3 protic and 8 aprotic solvents is examined against the reference RI-MP2/CBS method. The median Pearson correlation coefficients of ρ = 0.84 (GFN2-xTB) and ρ = 0.82 (GFN1-xTB) do not give the clear preference to any tested approach. GFN1-xTB method demonstrates more stable performance than its GFN2-xTB successor with the average mean absolute errors (MAEs)/mean signed errors (MSEs) of 1.2/0.2 and 2.3/1.6 kcal mol-1 , respectively. Conformational energies produced by the computationally efficient DFT functional PBE and double-ζ basis set complemented with -D3(BJ) dispersion correction are suitable for the preliminary sampling (median ρ = 0.93), but should be used with a caution for the calculations of the average ensemble properties (MAE/MSE = 1.7/1.1 kcal mol-1 ). Higher-ranking PBE0-D3(BJ) and ωB97M-V with triple-ζ basis sets yield significantly lower MAEs/MSEs of 0.55/0.20 and 0.51/0.23 kcal mol-1 , respectively.

We have investigated the adsorption of CH4 and CO2 gases on zinc oxide nanoclusters (ZnO NCs) using density functional theory (DFT). It was found that the CH4 tends to be physically adsorbed on the surface of all the ZnO NCs with adsorption energy in the range -11 to -14 kcal/mol. Even though, the CO2 is favorably chemisorbed on the Zn12 O12 and Zn15 O15 NCs, with adsorption energy about -38 kcal/mol at B3LYP/6-311G(d,p) level of theory. When the CH4 and CO2 gases are adsorbed on the ZnO NCs, their electrical conductivities are decreased, and thus the studied ZnO NCs do not generate an electrical signal in the presence of CH4 and CO2 gases. Interestingly, both pure and gas adsorbed Zn22 O22 NC exhibited more favorable electronic and reactive properties than other NCs. Comparison of the structural, electronic, and optical data predicted by DFT/B3LYP and TD-DFT/CAM-B3LYP calculations with those experimentally obtained show good agreement.

The π-complexes of cationic coinage metal ions (Cu(I), Ag(I), Au(I)) provide useful experimental support for understanding fundamental characteristics of bonding and 13 C-NMR patterns of the group 11 triad. Here, we account for the role of relativistic effects on olefin-coinage metal ion interaction for cationic, homoleptic tris-ethylene, and tris-norbornene complexes, [M(η2 -C2 H4 )3 ]+ and [M(η2 -C7 H10 )3 ]+ (M = Cu, Ag, Au), as representative case of studies. The M-(CC) bond strength in the cationic, tris-ethylene complexes is affected sizably for Au and to a lesser extent for Ag and Cu (48.6%, 16.7%, and 4.3%, respectively), owing to the influence on the different stabilizing terms accounting for the interaction energy in the formation of coinage metal cation-π complexes. The bonding elements provided by olefin → M σ-donation and olefin ← M π-backbonding are consequently affected, leading to a lesser covalent interaction going down in the triad if the relativistic effects are ignored. Analysis of the 13 C-NMR tensors provides further understanding of the observed experimental values, where the degree of backbonding charge donation to π2 *-olefin orbital is the main influence on the observed high-field shifts in comparison to the free olefin. This donation is larger for ethylene complexes and lower for norbornene counterparts. However, the bonding energy in the later complexes is slightly stabilized given by the enhancement in the electrostatic character of the interaction. Thus, the theoretical evaluation of metal-alkene bonds, and other metal-bonding situations, benefits from the incorporation of relativistic effects even in lighter counterparts, which have an increasing role going down in the group.

This work is focused on evaluating the performance of exchange-correlation functionals from density functional theory in providing descriptor values derived from the electron density of saddle point structures (transition states) in chemical reactions. The properties investigated were obtained from the quantum theory of atoms in molecules, including atomic charges and electron density topological data at the bond critical points. In addition, parameters from the Interacting quantum atom energy partition were used as well in this comparative study. The reference values are attained in coupled cluster calculations with iterative single and double excitations (CCSD). Six elementary reactions are considered here: CO + H2  ↔ H2 CO, CO + H2 O ↔ HCOOH, HCN ↔ HNC, H + F2  ↔ HF + F, H + N2  ↔ HN2 , and H + CO ↔ HCO. In general, the BB1K functional (hybrid-meta-generalized gradient approximation) provides the best description of these properties. Our study indicates that an intermediate percentage of nonlocal exact exchange, around 40%-55% (perhaps even larger), is probably required for attaining more accurate values with actual functionals, although this condition is not able of explaining all the trends observed.