A summary of the technical advances that are incorporated in the fourth major release of the Q-Chem quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and openshell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order Møller-Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly correlated Cr 2 dimer, exploring zeolitecatalysed ethane dehydrogenation, energy decomposition analysis of a charged ter-molecular complex arising from glycerol photoionisation, and natural transition orbitals for a Frenkel exciton state in a nine-unit model of a self-assembling nanotube.Keywords quantum chemistry, software, electronic structure theory, density functional theory, electron correlation, computational modelling, Q-Chem Disciplines Chemistry CommentsThis article is from Molecular Physics: An International Journal at the Interface Between Chemistry and Physics 113 (2015): 184, doi:10.1080/00268976.2014. RightsWorks produced by employees of the U.S. Government as part of their official duties are not copyrighted within the U.S. The content of this document is not copyrighted. Authors 185A summary of the technical advances that are incorporated in the fourth major release of the Q-CHEM quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and open-shell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order Møller-Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly corre...

Emitters placed in an optical cavity experience an environment that changes their coupling to light. In the weak-coupling regime light extraction is enhanced, but more profound effects emerge in the single-molecule strong-coupling regime where mixed light-matter states form1,2. Individual two-level emitters in such cavities become non-linear for single photons, forming key building blocks for quantum information systems as well as ultra-low power switches and lasers3–6. Such cavity quantum electrodynamics has until now been the preserve of low temperatures and complex fabrication, severely compromising their use5,7,8. Here, by scaling the cavity volume below 40 nm3 and using host-guest chemistry to align 1-10 protectively-isolated methylene-blue molecules, we reach the strong-coupling regime at room temperature and in ambient conditions. Dispersion curves from >50 plasmonic nanocavities display characteristic anticrossings, with Rabi frequencies of 300 meV for 10 molecules decreasing to 90 meV for single molecules, matching quantitative models. Statistical analysis of vibrational spectroscopy time-series and dark-field scattering spectra provide evidence of single-molecule strong coupling. This dressing of molecules with light can modify photochemistry, opening up the exploration of complex natural processes such as photosynthesis9 and pathways towards manipulation of chemical bonds10.

Advances in theory and algorithms for electronic structure calculations must be incorporated into program packages to enable them to become routinely used by the broader chemical community. This work reviews advances made over the past five years or so that constitute the major improvements contained in a new release of the Q-Chem quantum chemistry package, together with illustrative timings and applications. Specific developments discussed include fast methods for density functional theory calculations, linear scaling evaluation of energies, NMR chemical shifts and electric properties, fast auxiliary basis function methods for correlated energies and gradients, equation-of-motion coupled cluster methods for ground and excited states, geminal wavefunctions, embedding methods and techniques for exploring potential energy surfaces.

The nature of the hydrolysis of phosphate monoester dianions in solutions and in proteins is a problem of significant current interest. The present work explores this problem by systematic calculations of the potential surfaces of the reactions of a series of phosphate monoesters with different leaving groups. These calculations involve computational studies ranging from ab initio calculations with implicit solvent models to ab initio QM/MM free energy calculations. The calculations reproduce the observed linear free energy relationship (LFER) for the solution reaction and thus are consistent with the overall experimental trend and can be used to explore the nature of the transition state (TS) region, which is not accessible to direct experimental studies. It is found that the potential surface for the associative and dissociative paths is very flat and that the relative height of the associative and dissociative TS is different in different systems. In general, the character of the TS changes from associative to dissociative upon decrease in the pKa of the leaving group. It is also demonstrated that traditional experimental markers such as isotope effects and the LFER slope cannot be used in a conclusive way to distinguish between the two classes of transition states. In addition it is found that the effective charges of the TS do not follow the previously assumed simple rule. Armed with that experience we explore the free energy surface for the GTPase reaction of the RasGap system. In this case it is found that the surface is flat but that the lowest TS is associative. The present study indicates that the nature of the potential surfaces for the phosphoryl transfer reactions in solution and proteins is quite complicated and cannot be determined in a conclusive way without the use of careful theoretical studies that should, of course, reproduce the available experimental information.

We use quantum mechanics/molecular mechanics (QM/MM) simulations to study the cleavage of the ribonucleic acid (RNA) backbone catalyzed by ribonuclease H. This protein is a prototypical member of a large family of enzymes that use two-metal catalysis to process nucleic acids. By combining Hamiltonian replica exchange with a finite-temperature string method, we calculate the free energy surface underlying the RNA cleavage reaction and characterize its mechanism. We find that the reaction proceeds in two steps. In a first step, catalyzed primarily by magnesium ion A and its ligands, a water molecule attacks the scissile phosphate. Consistent with thiol-substitution experiments, a water proton is transferred to the downstream phosphate group. The transient phosphorane formed as a result of this nucleophilic attack decays by breaking the bond between the phosphate and the ribose oxygen. In the resulting intermediate, the dissociated but unprotonated leaving group forms an alkoxide coordinated to magnesium ion B. In a second step, the reaction is completed by protonation of the leaving group, with a neutral Asp132 as a likely proton donor. The overall reaction barrier of ~15 kcal mol−1, encountered in the first step, together with the cost of protonating Asp132, is consistent with the slow measured rate of ~1–100/min. The two-step mechanism is also consistent with the bell-shaped pH dependence of the reaction rate. The non-monotonic relative motion of the magnesium ions along the reaction pathway agrees with X-ray crystal structures. Proton transfer reactions and changes in the metal ion coordination emerge as central factors in the RNA cleavage reaction.

The hydrolysis of phosphate esters is crucially important to biological systems, being involved in, among other things, signaling, energy transduction, biosynthesis, and the regulation of protein function. Despite this, there are many questions that remain unanswered in this important field, particularly with regard to the preferred mechanism of hydrolysis of phosphate esters, which can proceed through any of multiple pathways that are either associative or dissociative in nature. Previous comparisons of calculated and observed linear free energy relationships (LFERs) for phosphate monoester dianions with different leaving groups showed that the TS character gradually changes from associative to dissociative with the increasing acidity of the leaving group, while reproducing the experimental LFER. Here, we have generated ab initio potential energy surfaces for the hydrolysis of phosphate diesters in solution, with a variety of leaving groups. Once again, the reaction changes from a compact concerted pathway to one that is more expansive in character when the acidity of the leaving group increases. When such systems are examined in solution, it is essential to take into consideration the contribution of solute to the overall activation entropy, which remains a major computational challenge. The popular method of calculating the entropy using a quasi-harmonic approximation appears to markedly overestimate the configurational entropy for systems with multiple occupied energy wells. We introduce an improved restraint release approach for evaluating configurational entropies and apply this approach to our systems. We demonstrate that when this factor is taken into account, it is possible to reproduce the experimental LFER for this system with reasonable accuracy.

Reliable studies of enzymatic reactions by combined quantum mechanical/molecular mechanics (QM/MM) approaches, with an ab initio description of the quantum region, presents a major challenge to computational chemists. The main problem is the need for a large amount of computer time to evaluate the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. This work presents major progress toward the evaluation of ab initio QM/MM free-energy surfaces and activation free energies of reactions in enzymes and in solutions. This is done by exploiting our previous idea of using the empirical valence bond (EVB) method as a reference potential and then using the linear response approximation (LRA) approach to evaluate the free energies of transfer from the EVB to the QM/MM surfaces in the reactant and product state. However, the new crucial step involves the use of a constraint at the transition state that fixes the system at a given value of the reaction coordinate and allows us to use the LRA at the transition state. The advance offered by the present approach is particularly significant because it evaluates the free energy associated with both the substrate and the solvent motions. This evaluation appeared to be a relatively simple task once one uses a classical reference potential. The main problem has been using the reference potential for the evaluation of the free-energy contributions associated with the solute motions where the difference between the reference EVB potential and the QM/MM potential can be large. The present refinement finally allows us to overcome the problems with the solute fluctuations and therefore to obtain, for the first time, a free-energy barrier that reflects the solute entropy properly. Thus, we present a way to evaluate the complete QM/MM activation free energy with an equal footing treatment of the solute and the solvent. This provides a general consistent and effective strategy for evaluating the QM/MM activation free energies in proteins and in solution. Our advance allows one to explore consistently various mechanistic and catalytic proposals while using ab initio (ai) QM/MM approaches.

The weighted histogram analysis method (WHAM) is widely used to obtain accurate free energies from biased molecular simulations. However, WHAM free energies can exhibit significant errors if some of the biasing windows are not fully equilibrated. To account for the lack of full equilibration, we develop the dynamic histogram analysis method (DHAM). DHAM uses a global Markov state model to obtain the free energy along the reaction coordinate. A maximum likelihood estimate of the Markov transition matrix is constructed by joint unbiasing of the transition counts from multiple umbrella-sampling simulations along discretized reaction coordinates. The free energy profile is the stationary distribution of the resulting Markov matrix. For this matrix, we derive an explicit approximation that does not require the usual iterative solution of WHAM. We apply DHAM to model systems, a chemical reaction in water treated using quantum-mechanics/molecular-mechanics (QM/MM) simulations, and the Na(+) ion passage through the membrane-embedded ion channel GLIC. We find that DHAM gives accurate free energies even in cases where WHAM fails. In addition, DHAM provides kinetic information, which we here use to assess the extent of convergence in each of the simulation windows. DHAM may also prove useful in the construction of Markov state models from biased simulations in phase-space regions with otherwise low population.