Projected Atomic Orbitals As Optimal Virtual Space for Excited State Projection-Based Embedding Calculations.

The projected atomic orbital (PAO) technique is presented for the construction of virtual orbital spaces in projection-based embedding (PbE) applications. The proposed straightforward procedure produces a set of virtual orbitals that are used in the final, high-level calculation of the embedded active subsystem. The PAO scheme is demonstrated on intermolecular potentials of bimolecular complexes in ground and excited states, including Rydberg excitations. The results show the outstanding performance of the PbE method when used with PAO virtual orbitals compared with those produced using common orbital localization techniques. The good agreement of the resulting PbE potential curves with those from high-level ab initio dimer calculations, also in diffuse basis sets, confirms that the PAO technique can be suggested for future applications using top-down embedding methods.

Development of analytic gradients for the Huzinaga quantum embedding method and its applications to large-scale hybrid and double hybrid DFT forces.

The theory of analytic gradients is presented for the projector-based density functional theory (DFT) embedding approach utilizing the Huzinaga-equation. The advantages of the Huzinaga-equation-based formulation are demonstrated. In particular, it is shown that the projector employed does not appear in the Lagrangian, and the potential risk of numerical problems is avoided at the evaluation of the gradients. The efficient implementation of the analytic gradient theory is presented for approaches where hybrid DFT, second-order Møller-Plesset perturbation theory, or double hybrid DFT are embedded in lower-level DFT environments. To demonstrate the applicability of the method and to gain insight into its accuracy, it is applied to equilibrium geometry optimizations, transition state searches, and potential energy surface scans. Our results show that bond lengths and angles converge rapidly with the size of the embedded system. While providing structural parameters close to high-level quality for the embedded atoms, the embedding approach has the potential to relax the coordinates of the environment as well. Our demonstrations on a 171-atom zeolite and a 570-atom protein system show that the Huzinaga-equation-based embedding can accelerate (double) hybrid gradient computations by an order of magnitude with sufficient active regions and enables affordable force evaluations or geometry optimizations for molecules of hundreds of atoms.

Basis Set Limit of CCSD(T) Energies: Explicit Correlation Versus Density-Based Basis-Set Correction.

A thorough comparison is carried out for explicitly correlated and density-based basis-set correction approaches, which were primarily developed to mitigate the basis-set incompleteness error of wave function methods. An efficient implementation of the density-based scheme is also presented, utilizing the density-fitting approximation. The performance of these approaches is comprehensively tested for the second-order Møller-Plesset (MP2), coupled-cluster singles and doubles (CCSD), and CCSD with perturbative triples [CCSD(T)] methods with respect to the corresponding complete basis set references. It is demonstrated that the density-based correction together with complementary auxiliary basis set (CABS)-corrected Hartree-Fock energies is highly robust and effectively reduces the error of the standard approaches; however, it does not outperform the corresponding explicitly correlated methods. Nevertheless, what still makes the density-corrected CCSD and CCSD(T) methods competitive is that their computational costs are roughly half of those of the corresponding explicitly correlated variants. Additionally, an incremental approach for standard CCSD and CCSD(T) is introduced. In this simple scheme, the total energies are corrected with the CABS correction and explicitly correlated MP2 contributions. As demonstrated, the resulting methods yield surprisingly good results, below 1 kcal/mol for thermochemical properties even with a double-ζ basis, while their computational expenses are practically identical to those of the density-based basis-set correction approaches.

Linear-Scaling Local Natural Orbital CCSD(T) Approach for Open-Shell Systems: Algorithms, Benchmarks, and Large-Scale Applications.

The extension of the highly optimized local natural orbital (LNO) coupled cluster (CC) with single-, double-, and perturbative triple excitations [LNO-CCSD(T)] method is presented for high-spin open-shell molecules based on restricted open-shell references. The techniques enabling the outstanding efficiency of the closed-shell LNO-CCSD(T) variant are adopted, including the iteration- and redundancy-free second-order Møller-Plesset and (T) formulations as well as the integral-direct, memory- and disk use-economic, and OpenMP-parallel algorithms. For large molecules, the efficiency of our open-shell LNO-CCSD(T) method approaches that of its closed-shell parent method due to the application of restricted orbital sets for demanding integral transformations and a novel approximation for higher-order long-range spin-polarization effects. The accuracy of open-shell LNO-CCSD(T) is extensively tested for radicals and reactions thereof, ionization processes, as well as spin-state splittings, and transition-metal compounds. At the size range where the canonical CCSD(T) reference is accessible (up to 20-30 atoms), the average open-shell LNO-CCSD(T) correlation energies are found to be 99.9 to 99.95% accurate, which translates into average absolute deviations of a few tenths of kcal/mol in the investigated energy differences already with the default settings. For more extensive molecules, the local errors may grow, but they can be estimated and decreased via affordable systematic convergence studies. This enables the accurate modeling of large systems with complex electronic structures, as illustrated on open-shell organic radicals and transition-metal complexes of up to 179 atoms as well as on challenging biochemical systems, including up to 601 atoms and 11,000 basis functions. While the protein models involve difficulties for local approximations, such as the spin states of a bounded iron ion or an extremely delocalized singly occupied orbital, the corresponding single-node LNO-CCSD(T) computations were feasible in a matter of days with 10s to 100 GB of memory use. Therefore, the new LNO-CCSD(T) implementation enables highly accurate computations for open-shell systems of unprecedented size and complexity with widely accessible hardware.

Vertical Ionization Potentials and Electron Affinities at the Double-Hybrid Density Functional Level.

The double-hybrid (DH) time-dependent density functional theory is extended to vertical ionization potentials (VIPs) and electron affinities (VEAs). Utilizing the density fitting approximation, efficient implementations are presented for the genuine DH ansatz relying on the perturbative second-order correction, while an iterative analogue is also elaborated using our second-order algebraic-diagrammatic construction [ADC(2)]-based DH approach. The favorable computational requirements of the present schemes are discussed in detail. The performance of the recently proposed spin-component-scaled and spin-opposite-scaled (SOS) range-separated (RS) and long-range corrected (LC) DH functionals is comprehensively assessed, while popular hybrid and global DH approaches are also discussed. For the benchmark calculations, up-to-date test sets are selected with high-level coupled-cluster references. Our results show that the ADC(2)-based SOS-RS-PBE-P86 approach is the most accurate and robust functional. This method consistently outperforms the excellent SOS-ADC(2) approach for VIPs, although the results are somewhat less satisfactory for VEAs. Among the genuine DH functionals, the SOS-ωPBEPP86 approach is also recommended for describing ionization processes, but its performance is even less reliable for electron-attached states. In addition, surprisingly good results are attained by the LC hybrid ωB97X-D functional, where the corresponding occupied (unoccupied) orbital energies are retrieved as VIPs (VEAs) within the present formalism.

Reduced-Cost Second-Order Algebraic-Diagrammatic Construction Method for Core Excitations.

Our reduced-cost scheme [J. Chem. Phys. 2018, 148, 094111] based on the frozen virtual natural orbital and natural auxiliary function approaches is extended to core excitations. The efficiency of the approximation is presented for the second-order algebraic-diagrammatic construction [ADC(2)] method invoking the core-valence separation (CVS) and density fitting approaches. The errors introduced by the present scheme are comprehensively analyzed for more than 200 excitation energies and 80 oscillator strengths, including C, N, and O K-edge excitations, as well as 1s → π* and Rydberg transitions. Our results show that significant savings can be gained in computational requirements at the expense of a moderate error. That is, the mean absolute error for the excitation energies, being lower than 0.20 eV, is an order of magnitude smaller than the intrinsic error of CVS-ADC(2), while the mean relative error for the oscillator strengths is between 0.06 and 0.08, which is still acceptable. As significant differences for different types of excitations cannot be observed, the robustness of the approximation is also demonstrated. The improvements in the computational requirements are measured for extended molecules. In this case, an overall 7-fold speedup is obtained in the wall-clock times, while dramatic reductions in the memory requirements are also achieved. In addition, it is also proved that the new approach enables us to perform CVS-ADC(2) calculations within reasonable runtime for systems of 100 atoms using reliable basis sets.

Turning Red without Feeling Embarrassed─Xanthenium-Based Photocages for Red-Light-Activated Phototherapeutics.

Herein, we present high-yielding, concise access to a set of xanthenium-derived, water-soluble, low-molecular-weight photocages allowing light-controlled cargo release in the green to red region. Very importantly, these new photocages allow installation of various payloads through ester, carbamate, or carbonate linkages even at the last stage of the synthesis. Payloads were uncaged with high efficiency upon green, orange, or red light irradiation, leading to the release of carboxylic acids, phenols, and amines. The near-ideal properties of a carboxanthenium derivative were further evaluated in the context of light-controlled drug release using a camptothecin-derived chemotherapeutic drug, SN38. Notably, the caged drug showed orders of magnitude lower efficiency in cellulo, which was reinstated after red light irradiation. The presented photocages offer properties that facilitate the translation of photoactivated chemotherapy toward clinical applications.

Double-Hybrid Density Functional Theory for Core Excitations: Theory and Benchmark Calculations.

The double-hybrid (DH) time-dependent density functional theory is extended to core excitations. Two different DH formalisms are presented utilizing the core-valence separation (CVS) approximation. First, a CVS-DH variant is introduced relying on the genuine perturbative second-order correction, while an iterative analogue is also presented using our second-order algebraic-diagrammatic construction [ADC(2)]-based DH ansatz. The performance of the new approaches is tested for the most popular DH functionals using the recently proposed XABOOM [J. Chem. Theory Comput.2021, 17, 1618] benchmark set. In order to make a careful comparison, the accuracy and precision of the methods are also inspected. Our results show that the genuine approaches are highly competitive with the more advanced CVS-ADC(2)-based methods if only excitation energies are required. In contrast, as expected, significant differences are observed in oscillator strengths; however, the precision is acceptable for the genuine functionals as well. Concerning the performance of the CVS-DH approaches, the PBE0-2/CVS-ADC(2) functional is superior, while its spin-opposite-scaled variant is also recommended as a cost-effective alternative. For these approaches, significant improvements are realized in the error measures compared with the popular CVS-ADC(2) method.

Analytic gradients for local density fitting Hartree-Fock and Kohn-Sham methods.

We present analytic gradients for local density fitting Hartree-Fock (HF) and hybrid Kohn-Sham (KS) density functional methods. Due to the non-variational nature of the local fitting algorithm, the method of Lagrange multipliers is used to avoid the solution of the coupled perturbed HF and KS equations. We propose efficient algorithms for the solution of the arising Z-vector equations and the gradient calculation that preserve the third-order scaling and low memory requirement of the original local fitting algorithm. In order to demonstrate the speed and accuracy of our implementation, gradient calculations and geometry optimizations are presented for various molecular systems. Our results show that significant speedups can be achieved compared to conventional density fitting calculations without sacrificing accuracy.

Basis Set Limit CCSD(T) Energies for Extended Molecules via a Reduced-Cost Explicitly Correlated Approach.

Several approximations are introduced and tested to reduce the computational expenses of the explicitly correlated coupled-cluster singles and doubles with perturbative triples [CCSD(T)] method for both closed and open-shell species. First, the well-established frozen natural orbital (FNO) technique is adapted to explicitly correlated CC approaches. Second, our natural auxiliary function (NAF) scheme is employed to reduce the size of the auxiliary basis required for the density fitting approximation regularly used in explicitly correlated calculations. Third, a new approach, termed the natural auxiliary basis (NAB) approximation, is proposed to decrease the size of the auxiliary basis needed for the expansion of the explicitly correlated geminals. The performance of the above approximations and that of the combined FNO-NAF-NAB approach are tested for atomization and reaction energies. Our results show that overall speedups of 7-, 5-, and 3-times can be achieved with double-, triple-, and quadruple-ζ basis sets, respectively, without any loss in accuracy. The new method can provide, e.g., reaction energies and barrier heights well within chemical accuracy for molecules with more than 40 atoms within a few days using a few dozen processor cores, and calculations with 50+ atoms are still feasible. These routinely affordable computations considerably extend the reach of explicitly correlated CCSD(T).

Performance of Multilevel Methods for Excited States.

The performance of multilevel quantum chemical approaches, which utilize an atom-based system partitioning scheme to model various electronic excited states, is studied. The considered techniques include the mechanical-embedding (ME) of "our own N-layered integrated molecular orbital and molecular mechanics" (ONIOM) method, the point charge embedding (PCE), the electronic-embedding (EE) of ONIOM, the frozen density-embedding (FDE), the projector-based embedding (PbE), and our local domain-based correlation method. For the investigated multilevel approaches, the second-order algebraic-diagrammatic construction [ADC(2)] approach was utilized as the high-level method, which was embedded in either Hartree-Fock or a density functional environment. The XH-27 test set of Zech et al. [ J. Chem. Theory Comput., 2018, 14, 4028] was used for the assessment, where organic dyes interact with several solvent molecules. With the selection of the chromophores as active subsystems, we conclude that the most reliable approach is local domain-based ADC(2) [L-ADC(2)], and the least robust schemes are ONIOM-ME and ONIOM-EE. The PbE, FDE, and PCE techniques often approach the accuracy of the L-ADC(2) scheme, but their precision is far behind. The results suggest that a more conservative subsystem selection algorithm or the inclusion of subsystem charge-transfers is required for the atom-based cost-efficient methods to produce high-accuracy excitation energies.

Implementation and Optimization of the Embedded Cluster Reference Interaction Site Model with Atomic Charges.

In this work, we implemented the embedded cluster reference interaction site model (EC-RISM) originally developed by Kloss, Heil, and Kast (J. Phys. Chem. B 2008, 112, 4337-4343). This method combines quantum mechanical calculations with the 3D reference interaction site model (3D-RISM). Numerous options, such as buffer, grid space, basis set, charge model, water model, closure relation, and so forth, were investigated to find the best settings. Additionally, the small point charges, which are derived from the solvent distribution from the 3D-RISM solution to represent the solvent in the QM calculation, were neglected to reduce the overhead without the loss of accuracy. On the MNSOL[a], MNSOL, and FreeSolv databases, our implemented and optimized method provides solvation free energies in water with 5.70, 6.32, and 6.44 kJ/mol root-mean-square deviations, respectively, but with different settings, 5.22, 6.08, and 6.63 kJ/mol can also be achieved. Only solvent models containing fitting parameters, like COSMO-RS and EC-RISM with universal correction and directly used electrostatic potential, perform better than our EC-RISM implementation with atomic charges.

Charge-Transfer Excitations within Density Functional Theory: How Accurate Are the Most Recommended Approaches?

The performance of the most recent density functionals is assessed for charge-transfer (CT) excitations using comprehensive intra- and intermolecular CT benchmark sets with high-quality reference values. For this comparison, the state-of-the-art range-separated (RS) and long-range-corrected (LC) double hybrid (DH) approaches are selected, and global DH and LC hybrid functionals are also inspected. The correct long-range behavior of the exchange-correlation (XC) energy is extensively studied, and various CT descriptors are compared as well. Our results show that the most robust performance is attained by RS-PBE-P86/SOS-ADC(2), as it is suitable to describe both types of CT excitations with outstanding accuracy. Furthermore, concerning the intramolecular transitions, unexpectedly excellent results are obtained for most of the global DHs, but their limitations are also demonstrated for bimolecular complexes. Despite the outstanding performance of the LC-DH methods for common intramolecular excitations, serious deficiencies are pointed out for intermolecular CT transitions, and the wrong long-range behavior of the XC energy is revealed. The application of LC hybrids to such transitions is not recommended in any respect.

Accurate Spectral Properties within Double-Hybrid Density Functional Theory: A Spin-Scaled Range-Separated Second-Order Algebraic-Diagrammatic Construction-Based Approach.

Our second-order algebraic-diagrammatic construction [ADC(2)]-based double-hybrid (DH) ansatz (J. Chem. Theory Comput. 2019, 15, 4440. DOI: 10.1021/acs.jctc.9b00391) is combined with range-separation techniques. In the present scheme, both the exchange and the correlation contributions are range-separated, while spin-scaling approaches are also applied. The new methods are thoroughly tested for the most popular benchmark sets including 250 singlet and 156 triplet excitations, as well as 80 oscillator strengths. It is demonstrated that the range separation for the correlation contributions is highly recommended for both the genuine and the ADC(2)-based DH approaches. Our results show that the latter scheme slightly but consistently outperforms the former one for single excitation dominated transitions. Furthermore, states with larger fractions of double excitations are assessed as well, and challenging charge-transfer excitations are also discussed, where the recently proposed spin-scaled long-range corrected DHs fail. The suggested iterative fourth-power scaling RS-PBE-P86/SOS-ADC(2) method, using only three adjustable parameters, provides the most robust and accurate excitation energies within the DH theory. In addition, the relative error of the oscillator strengths is reduced by 65% compared to the best genuine DH functionals.

Size-consistent explicitly correlated triple excitation correction.

A new approach is proposed to reduce the basis set incompleteness error of the triple excitation correction in explicitly correlated coupled-cluster singles and doubles with perturbative triples calculations. Our method is similar to the intuitive triples correction approach of Knizia et al. [J. Chem. Phys. 130, 054104 (2009)] but, in contrast to the latter, is size-consistent. The new approximation is easy to implement, and its overhead is negligible with respect to the conventional (T) correction. The performance of the approach is assessed for atomization, reaction, and interaction energies as well as for bond lengths and harmonic vibrational frequencies. The advantages of its size consistency are also demonstrated.

Oxygen Reduction Reaction on N-Doped Graphene: Effect of Positions and Scaling Relations of Adsorption Energies.

The goal of this study is to provide insight into the mechanism of the oxygen reduction reaction (ORR) on N-doped graphene surfaces. Using density functional theory and a computational hydrogen electrode model, we studied the energetics of the ORR intermediates, the effect of the position of the reaction site, and the effect of the position of the N modification relative to the active site on model graphene surfaces containing one or two N atoms. We found that scaling relations can be derived for N-doped graphenes as well, but the multiplicity of the surface should be taken into account. On the basis of the scaling relations between intermediates OOH* and OH*, the minimal overpotential is 0.33 V. Analysis of the data showed that N atoms in the meta position usually decrease the adsorption energy, but those in the ortho position aid the adsorption. The outer position on the zigzag edge of the graphene sheet also promotes the adsorption of oxygenated species, while the inner position hinders it. Looking at the most effective active sites, our analysis shows that the minimal overpotential can be approached with various doping arrangements, which also explains the contradicting results in the literature. The dissociative pathway was also investigated, but we found only one possible active site; therefore, this pathway is not really viable. However, routes not preferred thermodynamically pose the possibility of breaking the theoretical limit of the overpotential of the associative pathway.

Spin-Scaled Range-Separated Double-Hybrid Density Functional Theory for Excited States.

Our recently presented range-separated (RS) double-hybrid (DH) time-dependent density functional approach [J. Chem. Theory Comput. 17, 927 (2021)] is combined with spin-scaling techniques. The proposed spin-component-scaled (SCS) and scaled-opposite-spin (SOS) variants are thoroughly tested for almost 500 excitations including the most challenging types. This comprehensive study provides useful information not only about the new approaches but also about the most prominent methods in the DH class. The benchmark calculations confirm the robustness of the RS-DH ansatz, while several tendencies and deficiencies are pointed out for the existing functionals. Our results show that the SCS variant consistently improves the results, while the SOS variant preserves the benefits of the original RS-DH method reducing its computational expenses. It is also demonstrated that, besides our approaches, only the nonempirical functionals provide balanced performance for general applications, while particular methods are only suggested for certain types of excitations.

Interactions between large molecules pose a puzzle for reference quantum mechanical methods.

Quantum-mechanical methods are used for understanding molecular interactions throughout the natural sciences. Quantum diffusion Monte Carlo (DMC) and coupled cluster with single, double, and perturbative triple excitations [CCSD(T)] are state-of-the-art trusted wavefunction methods that have been shown to yield accurate interaction energies for small organic molecules. These methods provide valuable reference information for widely-used semi-empirical and machine learning potentials, especially where experimental information is scarce. However, agreement for systems beyond small molecules is a crucial remaining milestone for cementing the benchmark accuracy of these methods. We show that CCSD(T) and DMC interaction energies are not consistent for a set of polarizable supramolecules. Whilst there is agreement for some of the complexes, in a few key systems disagreements of up to 8 kcal mol-1 remain. These findings thus indicate that more caution is required when aiming at reproducible non-covalent interactions between extended molecules.

Speeding up Hartree-Fock and Kohn-Sham calculations with first-order corrections.

Several approaches are presented to improve the efficiency of Hartree-Fock and Kohn-Sham self-consistent field (SCF) calculations relying on a simple first-order energy correction reminiscent of the scheme used in dual-basis SCF methods. The basic idea is to perform an initial SCF calculation computing approximate Fock-matrices and, in the final iteration step, to use a more complete Fock-matrix builder together with the energy correction to diminish the error. The approximation is tested for conventional and local density fitting (DF) SCF approaches combining various auxiliary basis sets, fitting metrics, and Fock-matrix construction algorithms in the initial and final iterations as well as for seminumerical SCF methods combining integration grids of different qualities. We also report the implementation of the occupied orbital resolution of identity exchange construction algorithm with local DF approximations. Benchmark calculations are presented for total energies, reaction energies, and molecular geometries. Our results show that speedups of up to 80% can be expected utilizing the new approaches without significant loss of accuracy.

Linear-Scaling Open-Shell MP2 Approach: Algorithm, Benchmarks, and Large-Scale Applications.

A linear-scaling local second-order Møller-Plesset (MP2) method is presented for high-spin open-shell molecules based on restricted open-shell (RO) reference functions. The open-shell local MP2 (LMP2) approach inherits the iteration- and redundancy-free formulation and the completely integral-direct, OpenMP-parallel, and memory and disk use economic algorithms of our closed-shell LMP2 implementation. By utilizing restricted local molecular orbitals for the demanding integral transformation step and by introducing a novel long-range spin-polarization approximation, the computational cost of RO-LMP2 approaches that of closed-shell LMP2. Extensive benchmarks were performed for reactions of radicals, ionization potentials, as well as spin-state splittings of carbenes and transition-metal complexes. Compared to the conventional MP2 reference for systems of up to 175 atoms, local errors of at most 0.1 kcal/mol were found, which are well below the intrinsic accuracy of MP2. RO-LMP2 computations are presented for challenging protein models of up to 601 atoms and 11 000 basis functions, which involve either spin states of a complexed iron ion or a highly delocalized singly occupied orbital. The corresponding runtimes of 9-15 h obtained with a single, many-core CPU demonstrate that MP2, as well as spin-scaled MP2 and double-hybrid density functional methods, become widely accessible for open-shell systems of unprecedented size and complexity.