Search

This work addresses the pathological behavior of the energetics of dimethyl sulfoxide and related sulfur-containing compounds by providing the computational benchmark energetics of R2E2 species, where R = H/CH3 and E = O/S, with bent and pyramidal geometries using state-of-the-art methodologies. These 22 geometries were fully characterized with coupled-cluster with single, double, and perturbative triple excitations [CCSD(T)], second-order Moller–Plesset perturbation theory (MP2), and 22 density functional theory (DFT) methods with 8, 12, and 12, respectively, correlation consistent basis sets of double-, triple-, or quadruple-ζ quality. The relative energetics were determined at the MP2 and CCSD(T) complete basis set (CBS) limits using 17 basis sets up to sextuple-ζ and include augmented, tight-d, and core–valence correlation consistent basis sets. The relative energies of oxygen-/sulfur-containing compounds exhibit exceptionally slow convergence to the CBS limit with canonical methods as well as significant basis set dependence. CCSD(T) with quadruple-ζ basis sets can give qualitatively incorrect relative energies. Explicitly correlated MP2-F12 and CCSD(T)-F12 methods dramatically accelerate the convergence of the relative energies to the CBS limit for these problematic compounds. The F12 methods with a triple-ζ quality basis set give relative energies that deviate no more than 0.41 kcal mol−1 from the benchmark CBS limit. The correlation consistent Composite Approach (ccCA), ccCA-TM (TM for transition metals), and G3B3 deviated by no more than 2 kcal mol−1 from the benchmark CBS limits. Relative energies for oxygen-/sulfur-containing systems fully characterized with DFT are quite unreliable even with triple-ζ quality basis sets, and 13 out of 45 combinations fortuitously give a relative energy that is within 1 kcal mol−1 on average from the benchmark CCSD(T) CBS limit for these systems.

This work provides the first characterization of five stationary points of the homogeneous thioformaldehyde dimer, (CH2S)2, and seven stationary points of the heterogeneous formaldehyde/thioformaldehyde dimer, CH2O/CH2S, with correlated ab initio electronic structure methods. Full geometry optimizations and corresponding harmonic vibrational frequencies were computed with second-order Møller-Plesset perturbation theory (MP2) and 13 different density functionals in conjunction with triple-ζ basis sets augmented with diffuse and multiple sets of polarization functions. The MP2 results indicate that the three stationary points of (CH2S)2 and four of CH2O/CH2S are minima, in contrast to two stationary points of the formaldehyde dimer, (CH2O)2. Single-point energies were also computed using the explicitly correlated MP2-F12 and CCSD(T)-F12 methods and basis sets as large as heavy-aug-cc-pVTZ. The (CH2O)2 and CH2O/CH2S MP2 and MP2-F12 binding energies deviated from the CCSD(T)-F12 binding energies by no more than 0.2 and 0.4 kcal mol(-1), respectively. The (CH2O)2 and CH2O/CH2S global minimum is the same at every level of theory. However, the MP2 methods overbind (CH2S)2 by as much as 1.1 kcal mol(-1), effectively altering the energetic ordering of the thioformaldehyde dimer minima relative to the CCSD(T)-F12 energies. The CCSD(T)-F12 binding energies of the (CH2O)2 and CH2O/CH2S stationary points are quite similar, with the former ranging from around -2.4 to -4.6 kcal mol(-1) and the latter from about -1.1 to -4.4 kcal mol(-1). Corresponding (CH2S)2 stationary points have appreciably smaller CCSD(T)-F12 binding energies ranging from ca. -1.1 to -3.4 kcal mol(-1). The vibrational frequency shifts upon dimerization are also reported for each minimum on the MP2 potential energy surfaces.

DNA sequences with the potential to form secondary structures such as i-motifs (iMs) and G-quadruplexes (G4s) are abundant in the promoters of several oncogenes and, in some instances, are known to regulate gene expression. Recently, iM-forming DNA strands have also been employed as functional units in nanodevices, ranging from drug delivery systems to nanocircuitry. To understand both the mechanism of gene regulation by iMs and how to use them more efficiently in nanotechnological applications, it is essential to have a thorough knowledge of factors that govern their conformational states and stabilities. Most of the prior work to characterize the conformational dynamics of iMs have been done with iM-forming synthetic constructs like tandem (CCT)n repeats and in standard dilute buffer systems. Here, we present a systematic study on the consequences of epigenetic modifications, molecular crowding, and degree of hydration on the stabilities of an iM-forming sequence from the promoter of the c-myc gene. Our results indicate that 5-hydroxymethylation of cytosines destabilized the iMs against thermal and pH-dependent melting; contrarily, 5-methylcytosine modification stabilized the iMs. Under molecular crowding conditions (PEG-300, 40% w/v), the thermal stability of iMs increased by ∼10 °C, and the pKa was raised from 6.1 ± 0.1 to 7.0 ± 0.1. Lastly, the iM's stability at varying degrees of hydration in 1,2-dimethoxyethane, 2-methoxyethanol, ethylene glycol, 1,3-propanediol, and glycerol cosolvents indicated that the iMs are stabilized by dehydration because of the release of water molecules when folded. Our results highlight the importance of considering the effects of epigenetic modifications, molecular crowding, and the degree of hydration on iM structural dynamics. For example, the incorporation of 5-methylycytosines and 5-hydroxymethlycytosines in iMs could be useful for fine-tuning the pH- or temperature-dependent folding/unfolding of an iM. Variations in the degree of hydration of iMs may also provide an additional control of the folded/unfolded state of iMs without having to change the pH of the surrounding matrix.

This article details the re-examination of low-lying stationary points on the potential energy surfaces (PESs) of two challenging noncovalent homogeneous dimers, (P2)2 and (PCCP)2. The work was motivated by the rather large differences between MP2 and CCSD(T) energetics that were recently reported for these systems (J. Comput. Chem. 2014, 35, 479-487). The current investigation reveals significant qualitative and quantitative changes when the CCSD(T) method is used to characterize the stationary points instead of MP2. For example, CCSD(T) optimizations and harmonic vibrational frequency computations with the aug-cc-pVTZ basis set indicate that the parallel-slipped (PS) structure is the only P2 dimer stationary point examined that is a minimum (zero imaginary frequencies, ni = 0), whereas prior MP2 computations indicated that it was a transition state (ni = 1). Furthermore, the L-shaped structure of (P2)2 was the only minimum according to MP2 computations, but it collapses to the PS structure on the CCSD(T)/aug-cc-pVTZ PES. For the larger PCCP dimer, the CCSD(T) computations reveal that four rather than just two of the six stationary points characterized are minima. A series of explicitly correlated single-point energies were computed for all of the optimized structures to estimate the MP2 and CCSD(T) electronic energies at the complete basis set limit. CCSDT(Q) computations were also performed to assess the effects of dynamical electron correlation beyond the CCSD(T) level. For both (P2)2 and (PCCP)2, dispersion remains the dominant attractive component to the interaction energy according to symmetry-adapted perturbation theory analyses, and it is also the most challenging component to accurately evaluate.

Four unique gas phase mechanisms for peptide bond formation between two glycine molecules have been mapped out with quantum mechanical electronic structure methods. Both concerted and stepwise mechanisms, each leading to a cis and trans glycylglycine product (four mechanisms total), were examined with the B3LYP and MP2 methods and Gaussian atomic orbital basis sets as large as aug-cc-pVTZ. Electronic energies of the stationary points along the reaction pathways were also computed with explicitly correlated MP2-F12 and CCSD(T)-F12 methods. The CCSD(T)-F12 computations indicate that the electronic barriers to peptide bond formation are similar for all four mechanisms (ca. 32-39 kcal mol(-1) relative to two isolated glycine fragments). The smallest barrier (32 kcal mol(-1)) is associated with the lone transition state for the concerted mechanism leading to the formation of a trans peptide bond, whereas the largest barrier (39 kcal mol(-1)) was encountered along the concerted pathway leading to the cis configuration of the glycylglycine dipeptide. Two significant barriers are encountered for the stepwise mechanisms. For both the cis and trans pathways, the early electronic barrier is 36 kcal mol(-1) and the subsequent barrier is approximately 1 kcal mol(-1) lower. A host of intermediates and transition states lie between these two barriers, but they all have very small relative electronic energies (ca. ± 4 kcal mol(-1)). The isolated cis products (glycylglycine + H2O) are virtually isoenergetic with the isolated reactants (within -1 kcal mol(-1)), whereas the trans products are about 5 kcal mol(-1) lower in energy. In both products, however, the water can hydrogen bond to the dipeptide and lower the energy by roughly 5-9 kcal mol(-1). This study indicates that the concerted process leading to a trans configuration about the peptide bond is marginally favored both thermodynamically (exothermic by ca. 5 kcal mol(-1)) and kinetically (barrier height ≈ 32 kcal mol(-1)) according to the CCSD(T)-F12/haTZ electronic energies. The other pathways have slightly larger barrier heights (by 4-8 kcal mol(-1)).

A systematic study of cross-linking chemistry of the Au(25)(SR)(18) nanomolecule by dithiols of varying chain length, HS-(CH(2))(n)-SH where n = 2, 3, 4, 5, and 6, is presented here. Monothiolated Au(25) has six [RSAuSRAuSR] staple motifs on its surface, and MALDI mass spectrometry data of the ligand exchanged clusters show that propane (C3) and butane (C4) dithiols have ideal chain lengths for interstaple cross-linking and that up to six C3 or C4 dithiols can be facilely exchanged onto the cluster surface. Propanedithiol predominately exchanges with two monothiols at a time, making cross-linking bridges, while butanedithiol can exchange with either one or two monothiols at a time. The extent of cross-linking can be controlled by the Au(25)(SR)(18) to dithiol ratio, the reaction time of ligand exchange, or the addition of a hydrophobic tail to the dithiol. MALDI MS suggests that during ethane (C2) dithiol exchange, two ethanedithiols become connected by a disulfide bond; this result is supported by density functional theory (DFT) prediction of the optimal chain length for the intrastaple coupling. Both optical absorption spectroscopy and DFT computations show that the electronic structure of the Au(25) nanomolecule retains its main features after exchange of up to eight monothiol ligands.