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Free energy simulations that employ combined quantum mechanical and molecular mechanical (QM/MM) potentials at ab initio QM (AI) levels are computationally highly demanding. Here, we present a machine-learning-facilitated approach for obtaining AI/MM-quality free energy profiles at the cost of efficient semiempirical QM/MM (SE/MM) methods. Specifically, we use Gaussian process regression (GPR) to learn the potential energy corrections needed for an SE/MM level to match an AI/MM target along the minimum free energy path (MFEP). Force modification using gradients of the GPR potential allows us to improve configurational sampling and update the MFEP. To adaptively train our model, we further employ the sparse variational GP (SVGP) and streaming sparse GPR (SSGPR) methods, which efficiently incorporate previous sample information without significantly increasing the training data size. We applied the QM-(SS)GPR/MM method to the solution-phase SN2 Menshutkin reaction, N H 3 + C H 3 C l → C H 3 N H 3 + + C l − , using AM1/MM and B3LYP/6-31+G(d,p)/MM as the base and target levels, respectively. For 4000 configurations sampled along the MFEP, the iteratively optimized AM1-SSGPR-4/MM model reduces the energy error in AM1/MM from 18.2 to 4.4 kcal/mol. Although not explicitly fitting forces, our method also reduces the key internal force errors from 25.5 to 11.1 kcal/mol/ A ̊ and from 30.2 to 10.3 kcal/mol/ A ̊ for the N–C and C–Cl bonds, respectively. Compared to the uncorrected simulations, the AM1-SSGPR-4/MM method lowers the predicted free energy barrier from 28.7 to 11.7 kcal/mol and decreases the reaction free energy from −12.4 to −41.9 kcal/mol, bringing these results into closer agreement with their AI/MM and experimental benchmarks. [ABSTRACT FROM AUTHOR]

Plasmonic rulers (PRs) linking nanoscale distance dependence spectral shifts are important for studying cellular microenvironments and biomarker detection. The traditional PR design employs tethering metal nanoparticle pairs using synthetic and biopolymers that severely suffer from reproducibility issues, as well as lack reversibility. Here, the fabrication of novel PRs is reported through the formation of self‐assembled monolayers (SAMs) of photoswitchable molecular machines chemically tethered onto sharp‐tip gold nanostructures (Au NSs). This unique and highly sensitive PR utilizes localized surface plasmon resonance (LSPR) properties of Au NSs to spectroscopically evaluate dipole–dipole coupling between NSs and photoisomerizable spiropyran (SP)‐merocyanine (MC) conjugates in the solid‐state. It is observed that the SAM‐modified NSs are extremely sensitive to the photoisomerization of SP‐to‐MC, resulting in LSPR shifts as large as 5.6 nm for every 1.0 Å change in distance. The highly dipolar MC changes the NS‐SAM interfacial polarizability and alters the dipole–dipole coupling leading to the ultrasensitive PR is hypothesized. The hypothesis is supported theoretically by calculating dipole polarizability of an inorganic‐organic heterodimer model and experimentally by determining work function and interfacial dipole values. Taken together, this work represents the fabrication of next‐generation PRs, which hold great promise for advanced, plasmonic‐based sensors and optoelectronic device fabrication. [ABSTRACT FROM AUTHOR]

In combined quantum mechanical and molecular mechanical (QM/MM) free energy simulations, how to synthesize the accuracy of ab initio (AI) methods with the speed of semiempirical (SE) methods for a cost-effective QM treatment remains a long-standing challenge. In this work, we present a machine-learning-facilitated method for obtaining AI/MM-quality free energy profiles through efficient SE/MM simulations. In particular, we use Gaussian process regression (GPR) to learn the energy and force corrections needed for SE/MM to match with AI/MM results during molecular dynamics simulations. Force matching is enabled in our model by including energy derivatives into the observational targets through the extended-kernel formalism. We demonstrate the effectiveness of this method on the solution-phase SN2 Menshutkin reaction using AM1/MM and B3LYP/6-31+G(d,p)/MM as the base and target levels, respectively. Trained on only 80 configurations sampled along the minimum free energy path (MFEP), the resulting GPR model reduces the average energy error in AM1/MM from 18.2 to 5.8 kcal mol−1 for the 4000-sample testing set with the average force error on the QM atoms decreased from 14.6 to 3.7 kcal mol−1 Å−1. Free energy sampling with the GPR corrections applied (AM1-GPR/MM) produces a free energy barrier of 14.4 kcal mol−1 and a reaction free energy of −34.1 kcal mol−1, in closer agreement with the AI/MM benchmarks and experimental results. [ABSTRACT FROM AUTHOR]

[F.sub.o][F.sub.1]-ATP synthase manufactures the energy 'currency,' ATP, of living cells. The soluble [F.sub.1] portion, called [F.sub.1]-ATPase, can act as a rotary motor, with ATP binding, hydrolysis, and product release, inducing a torque on the [gamma]-subunit. A coarse-grained plastic network model is used to show at a residue level of detail how the conformational changes of the catalytic [beta]-subunits act on the [gamma]-subunit through repulsive van der Waals interactions to generate a torque that drives unidirectional rotation, as observed experimentally. The simulations suggest that the calculated 85[degrees] substep rotation is driven primarily by ATP binding and that the subsequent 35[degrees] substep rotation is produced by product release from one [beta]-subunit and a concomitant binding pocket expansion of another [beta]-subunit. The results of the simulation agree with single-molecule experiments [see, for example, Adachi K, et al. (2007) Cell 130:309-321] and support a tri-site rotary mechanism for [F.sub.1]-ATPase under physiological condition. ATP hydrolysis | coarse-grained | mechanical coupling | molecular motor | tri-site

Simulations of hydride and deuteride transfer catalyzed by dihydrofolate reductase from the hyperthermophile Thermotoga maritima (TmDHFR) are presented using ensemble-averaged variational transition theory with multidimensional tunneling. The results suggest that quantum mechanical tunneling makes a significant contribution to the reaction rate at all temperatures and dimerization is important for thermal stability of TmDHFR and its catalytic activity.

The generalized hybrid orbital (GHO) approach is used to combine a quantum mechanical (QM) fragment described by the self-consistent-charge density-functional tight-binding (SCC-DFTB) method with a fragment described by molecular mechanics. The results indicate that the GHO treatment for combining SCC-DFTB with molecular mechanics is both theoretically robust and satisfactory for practical use.

The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r-1 term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as a Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN2 reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN2 reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, theQM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of chemical reactions. [ABSTRACT FROM AUTHOR]

Image-potential states on Cu(111) surfaces covered by thin films of C[SUB60] fullerene have been characterized by angle-resolved two-photon photoemission spectroscopy. Metal-to-molecule electron transfer within the first layer creates a 4x4 superlattice of surface dipoles. We show that such a surface dipole lattice provides lateral confinement of image-electron wave functions. Measurements of parallel dispersion indicate that the n51 image state is localized in the presence of one monolayer of C[SUB60] but becomes delocalized by the addition of a second layer. Quantum mechanical calculations explain this in terms of the screening of the dipole potential, thus, restoring the free-electron behavior parallel to the surface. These results show that a surface dipole lattice can effectively control the interfacial electronic structure. [ABSTRACT FROM AUTHOR]

In previous work, three implicit potential energy surfaces with specific reaction parameters (SRP), namely MPW60, MC-QCISD-SRP, and MCG3-SRP, were developed for the reaction CH[sub 4]+H → CH[sub 3] + H[sub 2]. Forward reaction rate constants obtained by variational transition state theory with multidimensional tunneling (VTST/MT) dynamics calculations on these surfaces give good agreement with recently re-analyzed experimental results. In the present work, again employing VTST/MT, kinetic isotope effects (KIEs) for isotopic variants of the title reaction in both the forward and reverse directions are examined on these SRP surfaces. Various primary and secondary deuterium (D) kinetic isotope reactions are studied; we also calculated the KIE for the reaction between methane and muonium (Mu), which is an ultralight isotope of protium with the Mu/H mass ratio being 0.113. The results are compared with several sets of experimental studies. With the VTST/MT dynamical method and harmonic vibrations, the proposed surfaces predict the KIE quite well, probably within experimental error, for seven different isotopic combinations involving substitution of one to five deuteriums for protium. The calculations also reproduce quite well the high Arrhenius activation energy for Mu+CH[sub 4], and the KIE for muonium atom attack is correctly predicted to be inverse, but the predicted values of the Mu KIE over the experimental temperature range are 0.012-0.06 (without scaling force constants) or 0.021-0.09 (when the force constant of the making bond is scaled), whereas the experimental values in the same temperature range are 0.05-0.3. Several possible reasons for this are discussed. [ABSTRACT FROM AUTHOR]

Four implicit potential energy surfaces (PESs) with specific-reaction-parameters (SRP) are developed and tested for the reaction CH[sub 4]+H→CH[sub 3]+H[sub 2]. The first is called MPW60 and is based on the modified Perdew–Wang hybrid density-functional method with the percentage of the Hartree–Fock exchange equal to 60%. The other three PESs are constructed with multi-coefficient correlation methods (MCCMs). The second is called MCOMP2-SRP, and the third is called MC-QCISD-SRP. Both of them are parametrized for this specific reaction by starting with their corresponding global parameters. The fourth is called MCG3-SRP and is based on the MCG3-CHO semiglobal parametrization with further refinement for this specific reaction. All four SRP surfaces have a classical forward barrier height of 14.8 kcal/mol, and all three MCCM SRP surfaces have a classical endoergicity of 3.3 kcal/mol. The stationary point geometries, vibrational frequencies, and zero-point-energies are reported for several standard single-level methods and MCCMs with global parameters as well as for the four new SRP surfaces. Direct dynamics calculations are carried out using variational transition state theory with multidimensional tunneling contributions on the proposed SRP surfaces. We calculate forward reaction rate constants for the title reaction from 250 to 2400 K and compare them with the latest re-analyzed experimental results over the temperature range from 348 to 1950 K. The calculated rate constants using canonical variational theory with the small-curvature tunneling approximation carried out on the MPW60, MC-QCISD-SRP, and MCG3-SRP surfaces show good agreement with the experimental results. © 2002 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The efficiency of the multiconfiguration molecular mechanics method (MCMM) is improved by using electronic structure calculations only for certain critical elements of the Hessians at the nonstationary points and by using interpolation for the other elements at the nonstationary points. The new method yields quite accurate rate constants as compared with the standard MCMM strategy employing full electronic structure Hessians.

An efficient and accurate reference potential simulation protocol is proposed for producing ab initio quantum mechanical/molecular mechanical (AI-QM/MM) quality free energy profiles for chemical reactions in a solvent or macromolecular environment. This protocol involves three stages: (a) using force matching to recalibrate a semi-empirical quantum mechanical (SE-QM) Hamiltonian for the specific reaction under study; (b) employing the recalibrated SE-QM Hamiltonian (in combination with molecular mechanical force fields) as the reference potential to drive umbrella samplings along the reaction pathway; and (c) computing AI-QM/MM energy values for collected configurations from the sampling and performing weighted thermodynamic perturbation to acquire an AI-QM/MM corrected reaction free energy profile. For three model reactions (identity SN2 reaction, Menshutkin reaction, and glycine proton transfer reaction) in aqueous solution and one enzyme reaction (Claisen arrangement in chorismate mutase), our simulations using recalibrated PM3 SE-QM Hamiltonians well reproduced QM/MM free energy profiles at the B3LYP/6-31G* level of theory all within 1 kcal mol−1 with a 20 to 45 fold reduction in the computer time. [ABSTRACT FROM AUTHOR]

Variational transition state theory with multidimensional tunneling contributions (VTST/MT) is tested against quantum mechanical rate constants for the reaction H+CH[sub 4]→H[sub 2]+CH[sub 3] at temperatures up to 1000 K. The VTST/MT method can be and has been applied to many reactions that cannot be treated by rigorous quantum dynamics methods. Studying the accuracy of VTST/MT by comparison with accurate quantal results that are becoming available for systems of increasing size is important for validating the theory. In the present study, covering a factor of five in temperature, the VTST/MT method is found to have a mean deviation from accurate quantal rate constants for a six-body reaction of only 13% and maximum deviation of only 23%. [ABSTRACT FROM AUTHOR]