Surveying implicit solvent models for estimating small molecule absolute hydration free energies

Implicit solvent models are powerful tools in accounting for the aqueous environment at a fraction of the computational expense of explicit solvent representations. Here, we compare the ability of common implicit solvent models (TC, OBC, OBC2, GBMV, GBMV2, GBSW, GBSW/MS, GBSW/MS2 and FACTS) to reproduce experimental absolute hydration free energies for a series of 499 small neutral molecules that are modeled using AMBER/GAFF parameters and AM1-BCC charges. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, most implicit solvent models demonstrate reasonable agreement with extensive explicit solvent simulations (average difference 1.0-1.7 kcal/mol and R(2)=0.81-0.91) and with experimental hydration free energies (average unsigned errors=1.1-1.4 kcal/mol and R(2)=0.66-0.81). Chemical classes of compounds are identified that need further optimization of their ligand force field parameters and others that require improvement in the physical parameters of the implicit solvent models themselves. More sophisticated nonpolar models are also likely necessary to more effectively represent the underlying physics of solvation and take the quality of hydration free energies estimated from implicit solvent models to the next level.     

Conformational relaxation and water penetration coupled to ionization of internal groups in proteins

Molecular dynamics simulations were used to examine the effects of ionization of internal groups on the structures of eighteen variants of staphylococcal nuclease (SNase) with internal Lys, Asp, or Glu. In most cases the RMSD values of internal ionizable side chains were larger when the ionizable moieties were charged than when they were neutral. Calculations of solvent-accessible surface area showed that the internal ionizable side chains were buried in the protein interior when they were neutral and moved toward crevices and toward the protein-water interface when they were charged. The only exceptions are Lys-36, Lys-62, and Lys-103, which remained buried even after charging. With the exception of Lys-38, the number of internal water molecules surrounding the ionizable group increased upon charging: the average number of water oxygen atoms within the first hydration shell increased by 1.7 for Lys residues, by 5.2 for Asp residues, and by 3.2 for Glu residues. The polarity of the microenvironment of the ionizable group also increased when the groups were charged: the average number of polar atoms of any kind within the first hydration shell increased by 2.7 for Lys residues, by 4.8 for Asp residues, and by 4.0 for Glu residues. An unexpected correlation was observed between the absolute value of the shifts in pK(a) values measured experimentally, and several parameters of structural relaxation: the net difference in the polarity of the microenvironment of the charged and neutral forms of the ionizable groups, the net difference in hydration of the charged and neutral forms of the ionizable groups, and the difference in RMSD values of the charged and neutral forms of the ionizable groups. The effects of ionization of internal groups on the conformation of the backbone were noticeable but mostly small and localized to the area immediately next to the internal ionizable moiety. Some variants did exhibit local unfolding.     

Ground state 14N quadrupole couplings in the microwave spectra of N,N'-dimethylaniline and 4,4'-dimethylaminobenzonitrile

Microwave spectra of N,N'-dimethylaniline and 4,4'-dimethylaminobenzonitrile have been recorded in a pulsed supersonic jet using chirped pulse techniques. Experimental substitution structures have been determined for both molecules by detection of the spectra of all (13)C and (15)N isotopomers in natural abundance using a broadband spectrometer. Additionally, a narrowband spectrometer has been used to reveal the (14)N quadrupole splittings at high resolution, from which the orbital occupancy numbers of the amino- and cyano-nitrogen atoms have been determined. An apparent direct relationship between these values and the barriers to inversion of the amino groups is discussed.     

Rotational spectroscopy of iodobenzene and iodobenzene–neon with a direct digital 2–8 GHz chirped-pulse Fourier transform microwave spectrometer

The design of a chirped-pulse Fourier transform microwave spectrometer operating in the 2–8 GHz frequency range is presented. The linear frequency sweep is generated by an arbitrary waveform generator with a sampling rate of 20 GS/s. After amplification, the microwave pulse is broadcast into a vacuum chamber where it interacts with a supersonically expanded molecular sample. The resulting molecular free induction decay signal is amplified and digitized directly on a digital oscilloscope with a 20 GS/s sampling rate. No frequency mixing or multiplication is necessary in this spectrometer, which allows for very high pulse quality and phase stability. The performance of this spectrometer is demonstrated on the rotational spectrum of iodobenzene. All four distinct singly-substituted ¹³C isotopologues have been detected in natural abundance, as well as two isotopic species of a van der Waals cluster of iodobenzene with a neon atom. Spectroscopic constants and derived structural parameters for iodobenzene and for iodobenzene–Ne are reported. In addition, the use of microwave–microwave double-resonance experiments in this spectrometer to facilitate spectral assignments is presented.     

Cross section and parity-violating spin asymmetries of W± boson production in polarized p + p collisions at sqrt[s] = 500 GeV

Large parity-violating longitudinal single-spin asymmetries A(L)(e+) = -0.86(-0.14) (+0.30) and A(L)(e-) = 0.88(-0.71) (+0.12) are observed for inclusive high transverse momentum electrons and positrons in polarized p+p collisions at a center-of-mass energy of sqrt[s] = 500 GeV with the PHENIX detector at RHIC. These e± come mainly from the decay of W± and Z0 bosons, and their asymmetries directly demonstrate parity violation in the couplings of the W± to the light quarks. The observed electron and positron yields were used to estimate W± boson production cross sections for the e± channels of σ(pp → W+ X) × BR(W+ → e+ ν(e)) = 144.1 ± 21.2(stat)(-10.3) (+3.4) (syst) ± 21.6(norm) pb, and σ(pp → W- X) × BR(W- → e- ν[over ˉ](e)) = 31.7 ± 12.1(stat)(-8.2) (+10.1) (syst) ± 4.8(norm) pb.     

Assessing the quality of absolute hydration free energies among CHARMM‐compatible ligand parameterization schemes

Multipurpose atom‐typer for CHARMM (MATCH), an atom‐typing toolset for molecular mechanics force fields, was recently developed in our laboratory. Here, we assess the ability of MATCH‐generated parameters and partial atomic charges to reproduce experimental absolute hydration free energies for a series of 457 small neutral molecules in GBMV2, Generalized Born with a smooth SWitching (GBSW), and fast analytical continuum treatment of solvation (FACTS) implicit solvent models. The quality of hydration free energies associated with small molecule parameters obtained from ParamChem, SwissParam, and Antechamber are compared. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, these automated parameterization schemes with GBMV2 and GBSW demonstrate reasonable agreement with experimental hydration free energies (average unsigned errors of 0.9–1.5 kcal/mol and R² of 0.63–0.87). GBMV2 and GBSW consistently provide slightly more accurate estimates than FACTS, whereas Antechamber parameters yield marginally more accurate estimates than the current generation of MATCH, ParamChem, and SwissParam parameterization strategies. Modeling with MATCH libraries that are derived from different CHARMM topology and parameter files highlights the importance of having sufficient coverage of chemical space within the underlying databases of these automated schemes and the benefit of targeting specific functional groups for parameterization efforts to maximize both the breadth and the depth of the parameterized space. © 2013 Wiley Periodicals, Inc.     

Relaxing support vectors for classification

We introduce a novel modification to standard support vector machine (SVM) formulations based on a limited amount of penalty-free slack to reduce the influence of misclassified samples or outliers. We show that free slack relaxes support vectors and pushes them towards their respective classes, hence we use the name relaxed support vector machines (RSVM) for our method. We present theoretical properties of the RSVM formulation and develop its dual formulation for nonlinear classification via kernels. We show the connection between the dual RSVM and the dual of the standard SVM formulations. We provide error bounds for RSVM and show it to be stable, universally consistent and tighter than error bounds for standard SVM. We also introduce a linear programming version of RSVM, which we call RSVMLP. We apply RSVM and RSVMLP to synthetic data and benchmark binary classification problems, and compare our results with standard SVM classification results. We show that relaxed influential support vectors may lead to better classification results. We develop a two-phase method called RSVM² for multiple instance classification (MIC) problems, where RSVM formulations are used as classifiers. We extend the two-phase method to the linear programming case and develop RSVMLP². We demonstrate the classification characteristics of RSVM² and RSVMLP², and report our classification results compared to results obtained by other SVM-based MIC methods on public benchmark datasets. We show that both RSVM² and RSVMLP² are faster and produce more accurate classification results.     

Gallium Oxide Nanorods: Novel,Template‐Free Synthesis and High Catalytic Activity in Epoxidation Reactions

Gallium oxide nanorods with unprecedented small dimensions (20–80 nm length and 3–5 nm width) were prepared using a novel, template‐free synthesis method. This nanomaterial is an excellent heterogeneous catalyst for the sustainable epoxidation of alkenes with H₂O₂, rivaling the industrial benchmark microporous titanosilicate TS‐1 with linear alkenes and being much superior with bulkier substrates. A thorough characterization study elucidated the correlation between the physicochemical properties of the gallium oxide nanorods and their catalytic performance, and underlined the importance of the nanorod morphology for generating a material with high specific surface area and a high number of accessible acid sites.     

Revisiting the carboxylic acid dimers in aqueous solution: interplay of hydrogen bonding, hydrophobic interactions, and entropy

Carboxylic acid dimers are useful model systems for understanding the interplay of hydrogen bonding, hydrophobic effects, and entropy in self-association and assembly. Through extensive sampling with a classical force field and careful free energy analysis, it is demonstrated that both hydrogen bonding and hydrophobic interactions are indeed important for dimerization of carboxylic acids (except formic acid). The dimers are only weakly ordered, and the degree of ordering increases with stronger hydrophobic interactions between longer alkyl chains. Comparison of calculated and experimental dimerization constants reveals a systematic tendency for excessive self-aggregation in current classical force fields. Qualitative and quantitative information on the thermodynamics of hydrogen bonding and hydrophobic interactions derived from these simulations is in excellent agreement with existing results from experiment and theory. These results provide a verification from first principles of previous estimations based on two statistical mechanical hydrophobic theories. We also revisit and clarify the fundamental statistical thermodynamics formalism for calculating absolute binding constants, external entropy, and solvation entropy changes upon association from detailed free energy simulations. This analysis is believed to be useful for a wide range of applications including computational studies of protein-ligand and protein-protein binding.     

N-heterocyclic carbene-catalyzed oxidation of unactivated aldehydes to esters

N-Heterocyclic carbenes catalyze the oxidation of unactivated aldehydes to esters with manganese(IV) oxide in excellent yield. The reaction proceeds through a transient activated alcohol, which when generated in situ allows for the selective oxidation of the aldehyde under mild conditions. These conditions successfully oxidize potentially epimerizable aldehydes and alcohols while preserving stereochemical integrity. A variety of ester derivatives can be synthesized with variation of the acylated alcohol as well as the unactivated aldehyde.