Chirality-induced spin polarization places symmetry constraints on biomolecular interactions.

Noncovalent interactions between molecules are key for many biological processes. Necessarily, when molecules interact, the electronic charge in each of them is redistributed. Here, we show experimentally that, in chiral molecules, charge redistribution is accompanied by spin polarization. We describe how this spin polarization adds an enantioselective term to the forces, so that homochiral interaction energies differ from heterochiral ones. The spin polarization was measured by using a modified Hall effect device. An electric field that is applied along the molecules causes charge redistribution, and for chiral molecules, a Hall voltage is measured that indicates the spin polarization. Based on this observation, we conjecture that the spin polarization enforces symmetry constraints on the biorecognition process between two chiral molecules, and we describe how these constraints can lead to selectivity in the interaction between enantiomers based on their handedness. Model quantum chemistry calculations that rigorously enforce these constraints show that the interaction energy for methyl groups on homochiral molecules differs significantly from that found for heterochiral molecules at van der Waals contact and shorter (i.e., ∼0.5 kcal/mol at 0.26 nm).

The X40×10 Halogen Bonding Benchmark Revisited: Surprising Importance of (n-1)d Subvalence Correlation.

We have re-evaluated the X40×10 benchmark for halogen bonding using conventional and explicitly correlated coupled cluster methods. For the aromatic dimers at small separation, improved CCSD(T)-MP2 "high-level corrections" (HLCs) cause substantial reductions in the dissociation energy. For the bromine and iodine species, (n-1)d subvalence correlation increases dissociation energies and turns out to be more important for noncovalent interactions than is generally realized; (n-1)sp subvalence correlation is much less important. The (n-1)d subvalence term is dominated by core-valence correlation; with the smaller cc-pVDZ-F12-PP and cc-pVTZ-F12-PP basis sets, basis set convergence for the core-core contribution becomes sufficiently erratic that it may compromise results overall. The two factors conspire to generate discrepancies of up to 0.9 kcal/mol (0.16 kcal/mol RMS) between the original X40×10 data and the present revision.

Do CCSD and approximate CCSD-F12 variants converge to the same basis set limits? The case of atomization energies.

While the title question is a clear "yes" from purely theoretical arguments, the case is less clear for practical calculations with finite (one-particle) basis sets. To shed further light on this issue, the convergence to the basis set limit of CCSD (coupled cluster theory with all single and double excitations) and of different approximate implementations of CCSD-F12 (explicitly correlated CCSD) has been investigated in detail for the W4-17 thermochemical benchmark. Near the CBS ([1-particle] complete basis set) limit, CCSD and CCSD(F12*) agree to within their respective uncertainties (about ±0.04 kcal/mol) due to residual basis set incompleteness error, but a nontrivial difference remains between CCSD-F12b and CCSD(F12*), which is roughly proportional to the degree of static correlation. The observed basis set convergence behavior results from the superposition of a rapidly converging, attractive, CCSD[F12]-CCSD-F12b difference (consisting mostly of third-order terms) and a more slowly converging, repulsive, fourth-order difference between CCSD(F12*) and CCSD[F12]. For accurate thermochemistry, we recommend CCSD(F12*) over CCSD-F12b if at all possible. There are some indications that the nZaPa family of basis sets exhibits somewhat smoother convergence than the correlation consistent family.

The aug-cc-pVnZ-F12 basis set family: Correlation consistent basis sets for explicitly correlated benchmark calculations on anions and noncovalent complexes.

We have developed a new basis set family, denoted as aug-cc-pVnZ-F12 (or aVnZ-F12 for short), for explicitly correlated calculations. The sets included in this family were constructed by supplementing the corresponding cc-pVnZ-F12 sets with additional diffuse functions on the higher angular momenta (i.e., additional d-h functions on non-hydrogen atoms and p-g on hydrogen atoms), optimized for the MP2-F12 energy of the relevant atomic anions. The new basis sets have been benchmarked against electron affinities of the first- and second-row atoms, the W4-17 dataset of total atomization energies, the S66 dataset of noncovalent interactions, the Benchmark Energy and Geometry Data Base water cluster subset, and the WATER23 subset of the GMTKN24 and GMTKN30 benchmark suites. The aVnZ-F12 basis sets displayed excellent performance, not just for electron affinities but also for noncovalent interaction energies of neutral and anionic species. Appropriate CABSs (complementary auxiliary basis sets) were explored for the S66 noncovalent interaction benchmark: between similar-sized basis sets, CABSs were found to be more transferable than generally assumed.

The S66x8 benchmark for noncovalent interactions revisited: explicitly correlated ab initio methods and density functional theory.

The S66x8 dataset for noncovalent interactions of biochemical relevance has been re-examined by means of MP2-F12 and CCSD(F12*)(T) methods. We deem our revised benchmark data to be reliable to about 0.05 kcal mol(-1) RMS. Most levels of DFT perform quite poorly in the absence of dispersion corrections: somewhat surprisingly, that is even the case for the double hybrids and for dRPA75. Analysis of optimized D3BJ parameters reveals that the main benefit of dRPA75 and DSD double hybrids alike is the treatment of midrange dispersion. dRPA75-D3BJ is the best performer overall at RMSD = 0.10 kcal mol(-1). The nonlocal VV10 dispersion functional is especially beneficial for the double hybrids, particularly in DSD-PBEP86-NL (RMSD = 0.12 kcal mol(-1)). Other recommended dispersion-corrected functionals with favorable price/performance ratios are ωB97X-V, and, surprisingly, B3LYP-D3BJ and BLYP-D3BJ (RMSDs of 0.23, 0.20 and 0.23 kcal mol(-1), respectively). Without dispersion correction (but parametrized for midrange interactions) M06-2X has the lead (RMSD = 0.45 kcal mol(-1)). A collection of three energy-based diagnostics yields similar information to an SAPT analysis about the nature of the noncovalent interaction. Two of those are the percentages of Hartree-Fock and of post-MP2 correlation effects in the interaction energy; the third, CSPI = [IE - IE]/[IE + IE] or its derived quantity DEBC = CSPI/(1 + CSPI(2))(1/2), describes the character of the MP2 correlation contribution, ranging from 0 (purely dispersion) to 1 (purely other effects). In addition, we propose an improved, parameter-free scaling for the (T) contribution based on the Ecorr[CCSD-F12b]/Ecorr[CCSD] and Ecorr[CCSD(F12*)]/Ecorr[CCSD] ratios. For Hartree-Fock and conventional DFT calculations, full counterpoise generally yields the fastest basis set convergence, while for double hybrids, half-counterpoise yields faster convergence, as previously established for correlated ab initio methods.

Frequency and zero-point vibrational energy scale factors for double-hybrid density functionals (and other selected methods): can anharmonic force fields be avoided?

We have obtained uniform frequency scaling factors λ(harm) (for harmonic frequencies), λ(fund) (for fundamentals), and λ(ZPVE) (for zero-point vibrational energies (ZPVEs)) for the Weigend-Ahlrichs and other selected basis sets for MP2, SCS-MP2, and a variety of DFT functionals including double hybrids. For selected levels of theory, we have also obtained scaling factors for true anharmonic fundamentals and ZPVEs obtained from quartic force fields. For harmonic frequencies, the double hybrids B2PLYP, B2GP-PLYP, and DSD-PBEP86 clearly yield the best performance at RMSD = 10-12 cm(-1) for def2-TZVP and larger basis sets, compared to 5 cm(-1) at the CCSD(T) basis set limit. For ZPVEs, again, the double hybrids are the best performers, reaching root-mean-square deviations (RMSDs) as low as 0.05 kcal/mol, but even mainstream functionals like B3LYP can get down to 0.10 kcal/mol. Explicitly anharmonic ZPVEs only are marginally more accurate. For fundamentals, however, simple uniform scaling is clearly inadequate.

Hydrogen bonding interaction between active methylene hydrogen atoms and an anion as a binding motif for anion recognition: experimental studies and theoretical rationalization.

Two new reagents, having similar spatial arrangements for hydrogen atoms of the active methylene functionalities, were synthesized and interactions of such reagents with different anionic analytes were studied using electronic spectroscopy as well as by using (1)H and (31)P NMR spectroscopic methods. Experimental studies revealed that these two reagents showed preference for binding to F(-) and OAc(-). Detailed theoretical studies along with the above-mentioned spectroscopic studies were carried out to understand the contribution of the positively charged phosphonium ion, along with methylene functionality, in achieving the observed preference of these two receptors for binding to F(-) and OAc(-). Observed differences in the binding affinities of these two reagents toward fluoride and acetate ions also reflected the role of acidity of such methylene hydrogen atoms in controlling the efficiencies of the hydrogen bonding in anion-Hmethylene interactions. Hydrogen bonding interactions at lower concentrations of these two anionic analytes and deprotonation equilibrium at higher concentration were observed with associated electronic spectral changes as well as visually detectable change in solution color, an observation that is generally common for other strong hydrogen bond donor functionalities like urea and thiourea. DFT calculations performed with the M06/6-31+G**//M05-2X/6-31G* level of theory showed that F(-) binds more strongly than OAc(-) with the reagent molecules. The deprotonation of methylene hydrogen atom of receptors with F(-) ion was observed computationally. The metal complex as reagent showed even stronger binding energies with these analytes, which corroborated the experimental results.

Molecular interactions, proton exchange, and photoinduced processes prompted by an inclusion process and a [2]pseudorotaxane formation.

Appropriate design of the host and guest components allows formation of a novel [2]pseudorotaxane complex with an interrupted photoinduced electron transfer (PET)-coupled fluorescence resonance energy transfer (FRET) response. This is the first example of an inclusion complex with NO6-based azacrown ether as the host unit (H). Different guest molecules (G1, G2, G3, and G4) with varying stopper size are used for the studies. Unlike G1, G2, and G3, G4 with a relatively bulkier stopper fails to form a [2]pseudorotaxane complex. Isothermal titration microcalorimetry measurements reveal a systematic increase in the association constant for H·G1, H·G2, and H·G3 with a change in the stopper size. Thermodynamic data suggest that the formation of H·G1/H·G2/H·G3 is exclusively driven by a large positive entropic gain (TΔS = 19.69/26.80/21.81 kJ·mol(-1)), while the enthalpy change is slightly negative for H·G1/H·G3 (-2.61/-1.97 kJ·mol(-1)) and slightly positive for H·G2 (ΔH = 5.98 kJ·mol(-1)). For these three inclusion complexes, an interrupted PET-coupled FRET response is observed with varying efficiency, which is attributed to the subtle differences in acidity of the NH2(+) unit of the guest molecules and thus the proton exchange ability between the host and respective guest. This is substantiated by the results of the computational studies.

Ratiometric detection of Cr3+ and Hg2+ by a naphthalimide-rhodamine based fluorescent probe.

Newly synthesized rhodamine derivatives, L(1) and L(2), are found to bind specifically to Hg(2+) or Cr(3+) in presence of large excess of other competing ions with associated changes in their optical and fluorescence spectral behavior. These spectral changes are significant enough in the visible region of the spectrum and thus, allow the visual detection. For L(1), the detection limit is even lower than the permissible [Cr(3+)] or [Hg(2+)] in drinking water as per standard U.S. EPA norms; while the receptor, L2 could be used as a ratiometric sensor for detection of Cr(3+) and Hg(2+) based on the resonance energy transfer (RET) process involving the donor naphthalimide and the acceptor Cr(3+)/Hg(2+)-bound xanthene fragment. Studies reveal that these two reagents could be used for recognition and sensing of Hg(2+)/Cr(3+). Further, confocal laser microscopic studies confirmed that the reagent L(2) could also be used as an imaging probe for detection of uptake of these ions in A431 cells.

An alternative approach: a highly selective dual responding fluoride sensor having active methylene group as binding site.

A newly designed phosphonium derivative (L) having active methylene functionality, shows unusual preference towards F(-) over all other anions. The binding process through C-H···F(-) hydrogen bond formation was probed by monitoring the changes in either electronic or luminescence spectra. Changes in both cases are significant enough to allow visual detection. The loss of molecular flexibility of L on forming L·F(-) effectively interrupts the non-radiative deactivation pathway and accounts for the observed switch on fluorescence response. The results of the time-resolved emission studies for L and L·F(-) using a time-correlated single photon counting technique further corroborate this presumption. The excellent preference of L towards F(-) is attributed to an efficient hydrogen bonding interaction between the strongly polarized methylene protons and F(-), which delineates the subtle difference in the affinity among other competing anionic analytes like CN(-), H(2)PO(4)(-), CH(3)CO(2)(-), etc. The relative affinities of various anions and the preferential binding of F(-) to reagent L are also rationalized using computational studies.

Probing the structural and electronic effects to stabilize nonplanar forms of thioamide derivatives: a computational study.

Density functional calculations have been performed to examine the stability of nonplanar conformations of thioamide derivatives. Electrostatic, orbital, and ring strain effects were invoked to stabilize the nonplanar conformations of thioamide systems 2-7. Electrostatic interactions helped to achieve the twisted forms of thioamide derivatives; however, pyramidal forms predicted to be the global minimum. Negative hyperconjugative type interactions enhanced the stability of the twisted form 4b when compared with the planar form 4a. The influence of ring strain effect to achieve the twisted form of thioamide was observed with azirine ring. The predictions made with B3LYP/cc-pVDZ+ level of theory was found to be in good agreement with more accurate CBS-QB3 method. The solvent calculations performed with polarized continuum solvation model suggest that the relative stabilities of the nonplanar forms of thioamide derivatives are in general similar to the gas phase results. The importance of hydrogen bonding interactions between the solvent molecules and thioamide derivatives was observed toward the enhanced stability of twisted forms using a combination of explicit solvent molecules and continuum model. The natural bond orbital analysis confirmed the participation of n(N) → π*(C=S) delocalizations in the planar forms and corroborated the earlier reports on larger delocalizations in thioamide systems. Furthermore, the influence of electrostatic and ring strain effects on the amide, natural amides, and selenoamide has also been studied.

Folding and unfolding movements in a [2]pseudorotaxane.

A new dibenzo[24]crown-8 derivative (1) was synthesized and functionalized with aromatic moieties such as naphthalene and coumarin units. These two fluorophores are known to form an effective FRET (Forster resonance energy transfer) pair, and this formed the basis for the design of this host crown ether derivative. Results of the steady-state and time-resolved fluorescence studies confirmed the resonance energy transfer between the donor naphthalene moiety and acceptor coumarin fragment, while NMR spectra and computational studies support a folded conformation for the uncomplexed crown ether 1. This was found to form an inclusion complex, a [2]pseudorotaxane type with imidazolium ion derivatives as the guest molecules with varying alkyl chain lengths ([C(4)mim](+) or [C(10)mim](+)). The host crown ether (1) tends to adopt an open conformation on formation of the interwoven inclusion complex (1·[C(4)mim](+) or 1·[C(10)mim](+)). This change in conformation, from the folded to a open one, was predicted by computational as well as (1)H NMR studies and was confirmed by single crystal X-ray structure for one (1·[C(4)mim](+)) of the two inclusion complexes. The increase in the effective distance between the naphthalene and coumarin moieties in the open conformation of these inclusion complexes was also supported by the decrease in the effective FRET process that was operational between naphthalene and coumarin moieties in the free molecule (1). Importantly, this inclusion complex formation was found to be reversible, and in the presence of a stronger base/polar solvent, such as triethyl amine/DMSO, the deprotonation/effective solvation of the cationic imidizolium ions ([C(4)mim](+) or [C(10)mim](+)) resulted in decomplexation or dethreading with restoration of the original emission spectra for 1, which signifies the subsequent increase in the FRET process. Thus we could demonstrate that a molecular folding-unfolding type of movement in the crown ether derivative could be induced by chemical input as an imidazolium ion.

An experimental and theoretical study on the remarkable influence of protecting groups on the selectivity of addition of amines to vinyl sulfone-modified hex-2-enopyranosides.

Although phenylmethylene-protected vinyl sulfone-modified carbohydrate 2alpha reacts with both primary and secondary amines in Michael fashion to afford aminated products, only primary amines react with the dibenzyl-protected 3alpha, 6-O-trityl-protected 4alpha, and unprotected 5alpha, highlighting for the first time the remarkable influence of protecting groups on the reaction patterns of vinyl sulfone-modified carbohydrates. The quantum chemical calculations suggest that the Michael addition of amines and proton transfer to vinyl sulfone-modified carbohydrates 2alpha and 5alpha are possible via relay process in a concerted mechanism. These calculations reveal that the addition of primary amines to vinyl sulfone-modified carbohydrate is preferential due to the low activation energy barriers, whereas the addition of secondary amines has relatively higher activation energy barriers. The theoretical conclusions are in line with the experimental observations.

Probing the influence of anomeric effects on the lithium ion affinity in 1,3-diaza systems: a computational study.

Lithium ion affinities of methanediamine (MDA), N,N,N',N'-tetramethylmethanediamine (TMMDA), 1,3-diazacyclohexane (DAC), trans-3,5-diazabicyclo[4.4.0]decane (trans-3,5-DBD), trans-1,3-diazabicyclo[4.4.0]decane (trans-1,3-DBD), cis-1,3-diazabicyclo[4.4.0]decane (cis-1,3-DBD), 1,5-diazabicyclo[3.3.1]nonane (DBN), trans-decahydro-8a,9a-diazaanthracene (trans-DDA), cis-decahydro-8a,9a-diazaanthracene (cis-DDA), 1,3-diazetidine (DAT), 1,3-imidazolidine (IMD), and 1,3-diazepane (DAP) have been studied by using density functional theory (DFT) and correlated ab initio methods. Possible conformers of these compounds were optimized at the B3LYP/6-31+G* level, and relative energies were evaluated at the MP2/6-311+G**//B3LYP/6-31+G* level. The experimental lithium ion affinities for reference molecules (i.e., ammonia and trimethylamine) are well-reproduced at these levels of theory. NBO analysis shows the influence of anomeric effects (n(N) → σ*(C-N) hyperconjugative interactions) on the conformational stability of the title compounds; however, the electrostatic and steric contributions included in the NBO Lewis term also affect the stabilities in some cases. The influence of anomeric effect is apparent in cis-DDA, where the nitrogen involved in n(N) → σ*(C-N) hyperconjugative interaction (cis-DDA-Li2) has a lithium ion affinity 1.7 kcal/mol lower than the nitrogen not involved in n(N) → σ*(C-N) hyperconjugative interaction (cis-DDA-Li1). In general, the computed lithium ion affinities were found to be conformationally dependent. The NBO results showed that the lithium ion affinities are also governed by the interplay of n(N) → σ*(C-N) hyperconjugative interactions and the steric strain caused upon lithiation. Further, the ring size also influences the lithium ion affinities in the 1,3-diaza monocyclic systems. In some complexes multiple coordination of the lithium ion is possible by inversion of one of the nitrogen atoms.

Differential binding of bispyridinium oxime drugs with acetylcholinesterase.

AIM: To performe a time-dependent topographical delineation of protein-drug interactions to gain molecular insight into the supremacy of Ortho-7 over HI-6 in reactivating tabun-conjugated mouse acetylcholinesterase (mAChE). METHODS: We conducted all-atom steered molecular dynamics simulations of the two protein-drug complexes. Through a host of protein-drug interaction parameters (rupture force profiles, hydrogen bonds, water bridges, hydrophobic interactions), geometrical, and orientation ordering of the drugs, we monitored the enzyme's response during the release of the drugs from its active-site. RESULTS: The results show the preferential binding of the drugs with the enzyme. The pyridinium ring of HI-6 shows excellent complementary binding with the peripheral anionic site, whereas one of two identical pyridinium rings of Ortho-7 has excellent binding compatibility in the enzyme active-site where it can orchestrate the reactivation process. We found that the active pyridinium ring of HI-6 undergoes a complete turn along the active site axis, directed away from the active-site region during the course of the simulation. CONCLUSION: Due to excellent cooperative binding of Ortho-7, as rendered by several cation-pi interactions with the active-site gorge of the enzyme, Ortho-7 may be a more efficient reactivator than HI-6. Our work supports the growing body of evidence that the efficacy of the drugs is due to the differential bindings of the oximes with AChE and can aid to the rational design of oxime drugs.

Conventional and Explicitly Correlated ab Initio Benchmark Study on Water Clusters: Revision of the BEGDB and WATER27 Data Sets.

Benchmark ab initio energies for BEGDB and WATER27 data sets have been re-examined at the MP2 and CCSD(T) levels with both conventional and explicitly correlated (F12) approaches. The basis set convergence of both conventional and explicitly correlated methods has been investigated in detail, both with and without counterpoise corrections. For the MP2 and CCSD-MP2 contributions, rapid basis set convergence observed with explicitly correlated methods is compared to conventional methods. However, conventional, orbital-based calculations are preferred for the calculation of the (T) term, since it does not benefit from F12. CCSD(F12*) converges somewhat faster with the basis set than CCSD-F12b for the CCSD-MP2 term. The performance of various DFT methods is also evaluated for the BEGDB data set, and results show that Head-Gordon's ωB97X-V and ωB97M-V functionals outperform all other DFT functionals. Counterpoise-corrected DSD-PBEP86 and raw DSD-PBEPBE-NL also perform well and are close to MP2 results. In the WATER27 data set, the anionic (deprotonated) water clusters exhibit unacceptably slow basis set convergence with the regular cc-pVnZ-F12 basis sets, which have only diffuse s and p functions. To overcome this, we have constructed modified basis sets, denoted aug-cc-pVnZ-F12 or aVnZ-F12, which have been augmented with diffuse functions on the higher angular momenta. The calculated final dissociation energies of BEGDB and WATER27 data sets are available in the Supporting Information. Our best calculated dissociation energies can be reproduced through n-body expansion, provided one pushes to the basis set and electron correlation limit for the two-body term; for the three-body term, post-MP2 contributions (particularly CCSD-MP2) are important for capturing the three-body dispersion effects. Terms beyond four-body can be adequately captured at the MP2-F12 level.

Benchmark ab Initio Conformational Energies for the Proteinogenic Amino Acids through Explicitly Correlated Methods. Assessment of Density Functional Methods.

The relative energies of the YMPJ conformer database of the 20 proteinogenic amino acids, with N- and C-termination, have been re-evaluated using explicitly correlated coupled cluster methods. Lower-cost ab initio methods such as MP2-F12 and CCSD-F12b actually are outperformed by double-hybrid DFT functionals; in particular, the DSD-PBEP86-NL double hybrid performs well enough to serve as a secondary standard. Among range-separated hybrids, ωB97X-V performs well, while B3LYP-D3BJ does surprisingly well among traditional DFT functionals. Treatment of dispersion is important for the DFT functionals; for the YMPJ set, D3BJ generally works as well as the NL nonlocal dispersion functional. Basis set sensitivity for DFT calculations on these conformers is weak enough that def2-TZVP is generally adequate. For conformer corrections to heats of formation, B3LYP-D3BJ and especially DSD-PBEP86-D3BJ or DSD-PBEP86-NL are adequate for all but the most exacting applications. The revised geometries and energetics for the YMPJ database have been made available as Supporting Information and should be useful in the parametrization and validation of molecular mechanics force fields and other low-cost methods. The very recent dRPA75 method yields good performance, without resorting to an empirical dispersion correction, but is still outperformed by DSD-PBEP86-D3BJ and particularly DSD-PBEP86-NL. Core-valence corrections are comparable in importance to improvements beyond CCSD(T*)/cc-pVDZ-F12 in the valence treatment.

Exploring the Accuracy Limits of Local Pair Natural Orbital Coupled-Cluster Theory.

The domain based local pair natural orbital coupled cluster method with single-, double-, and perturbative triple excitations (DLPNO­CCSD(T)) is an efficient quantum chemical method that allows for coupled cluster calculations on molecules with hundreds of atoms. Because coupled-cluster theory is the method of choice if high-accuracy is needed, DLPNO­CCSD(T) is very promising for large-scale chemical application. However, the various approximations that have to be introduced in order to reach near linear scaling also introduce limited deviations from the canonical results. In the present work, we investigate how far the accuracy of the DLPNO­CCSD(T) method can be pushed for chemical applications. We also address the question at which additional computational cost improvements, relative to the previously established default scheme, come. To answer these questions, a series of benchmark sets covering a broad range of quantum chemical applications including reaction energies, hydrogen bonds, and other noncovalent interactions, conformer energies, and a prototype organometallic problem were selected. An accuracy of 1 kcal/mol or better can readily be obtained for all data sets using the default truncation scheme, which corresponds to the stated goal of the original implementation. Tightening of the three thresholds that control DLPNO leads to mean absolute errors and standard deviations from the canonical results of less than 0.25 kcal/mol (<1 kJ/mol). The price one has then to pay is an increased computational time by a factor close to 3. The applicability of the method is shown to be independent of the nature of the reaction. On the basis of the careful analysis of the results, three different sets of truncation thresholds (termed "LoosePNO", "NormalPNO", and "TightPNO") have been chosen for "black box" use of DLPNO­CCSD(T). This will allow users of the method to optimally balance performance and accuracy.

Assessment of CCSD(T)-F12 Approximations and Basis Sets for Harmonic Vibrational Frequencies.

We consider basis set convergence and the effect of various approximations to CCSD(T)-F12 for a representative sample of harmonic frequencies (the HFREQ2014 set). CCSD(T*)(F12*)/cc-pVDZ-F12 offers a particularly favorable compromise between accuracy and computational cost: its RMSD <3 cm(-1) from the valence CCSD(T) limit is actually less than the remaining discrepancy with the experimental value at the valence CCSD(T) limit (about 5 cm(-1) RMSD). CCSD(T)-F12a and CCSD(T)-F12b appear to benefit from error compensation between CCSD and (T).