Molecular dynamics study of the proposed proton transport pathways in [FeFe]-hydrogenase.

Possible proton transport pathways in Clostridium pasteurianum (CpI) [FeFe]-hydrogenase were investigated with molecular dynamics simulations. This study was undertaken to evaluate the functional pathway and provide insight into the hydrogen bonding features defining an active proton transport pathway. Three pathways were evaluated, two of which consist of water wires and one of predominantly amino acid residues. Our simulations suggest that protons are not transported through water wires. Instead, the five-residue motif (Glu282, Ser319, Glu279, H2O, Cys299) was found to be the likely pathway, consistent with previously made experimental observations. The pathway was found to have a persistent hydrogen bonded core (residues Cys299 to Ser319), with less persistent hydrogen bonds at the ends of the pathway for both H2 release and H2 uptake. Single site mutations of the four residues have been shown experimentally to deactivate the enzyme. The theoretical evaluation of these mutations demonstrates redistribution of the hydrogen bonds in the pathway, resulting in enzyme deactivation. Finally, coupling between the protein dynamics near the proton transport pathway and the redox partner binding regions was also found as a function of H2 uptake and H2 release states, which may be indicative of a correlation between proton and electron movement within the enzyme.

Beyond the active site: the impact of the outer coordination sphere on electrocatalysts for hydrogen production and oxidation.

Redox active metalloenzymes play a major role in energy transformation reactions in biological systems. Examples include formate dehydrogenases, nitrogenases, CO dehydrogenase, and hydrogenases. Many of these reactions are also of interest to humans as potential energy storage or utilization reactions for photoelectrochemical, electrolytic, and fuel cell applications. These metalloenzymes consist of redox active metal centers where substrates are activated and undergo transformation to products accompanied by electron and proton transfer to or from the substrate. These active sites are typically buried deep within a protein matrix of the enzyme with channels for proton transport, electron transport, and substrate/product transport between the active site and the surface of the protein. In addition, there are amino acid residues that lie in close proximity to the active site that are thought to play important roles in regulating and enhancing enzyme activity. Directly studying the outer coordination sphere of enzymes can be challenging due to their complexity, and the use of modified molecular catalysts may allow us to provide some insight. There are two fundamentally different approaches to understand these important interactions. The "bottom-up" approach involves building an amino acid or peptide containing outer coordination sphere around a functional molecular catalyst, and the "top-down" approach involves attaching molecular catalyst to a structured protein. Both of these approaches have been undertaken for hydrogenase mimics and are the emphasis of this Account. Our focus has been to utilize amino acid or peptide based scaffolds on an active functional enzyme mimic for H2 oxidation and production, [Ni(P(R)2N(R('))2)2](2+). This "bottom-up" approach has allowed us to evaluate individual functional group and structural contributions to electrocatalysts for H2 oxidation and production. For instance, using amine, ether, and carboxylic acid functionalities in the outer coordination sphere enhances proton movement and results in lower catalytic overpotentials for H2 oxidation, while achieving water solubility in some cases. Amino acids with acidic and basic side chains concentrate substrate around catalysts for H2 production, resulting in up to 5-fold enhancements in rate. The addition of a structured peptide in an H2 production catalyst limited the structural freedom of the amino acids nearest the active site, while enhancing the overall rate. Enhanced stability to oxygen or extreme conditions such as strongly acidic or basic conditions has also resulted from an amino acid based outer coordination sphere. From the "top-down" approach, others have achieved water solubility and photocatalytic activity by associating this core complex with photosystem-I. Collectively, by use of this well understood core, the role of individual and combined features of the outer coordination sphere are starting to be understood at a mechanistic level. Common mechanisms have yet to be defined to predictably control these processes, but our growing knowledge in this area is essential for the eventual mimicry of enzymes by efficient molecular catalysts for practical use.

Enzyme design from the bottom up: an active nickel electrocatalyst with a structured peptide outer coordination sphere.

Catalytic, peptide-containing metal complexes with a well-defined peptide structure have the potential to enhance molecular catalysts through an enzyme-like outer coordination sphere. Here, we report the synthesis and characterization of an active, peptide-based metal complex built upon the well-characterized hydrogen production catalyst [Ni(P(Ph)2N(Ph))2](2+) (P(Ph)2N(Ph)=1,3,6-triphenyl-1-aza-3,6-diphosphacycloheptane). The incorporated peptide maintains its ß-hairpin structure when appended to the metal core, and the electrocatalytic activity of the peptide-based metal complex (≈100,000 s(-1)) is enhanced compared to the parent complex ([Ni(P(Ph)2N(APPA))2](2+); ≈50,500 s(-1)). The combination of an active molecular catalyst with a structured peptide provides a scaffold that permits the incorporation of features of an enzyme-like outer-coordination sphere necessary to create molecular electrocatalysts with enhanced functionality.

In silico identification software (ISIS): a machine learning approach to tandem mass spectral identification of lipids.

MOTIVATION: Liquid chromatography-mass spectrometry-based metabolomics has gained importance in the life sciences, yet it is not supported by software tools for high throughput identification of metabolites based on their fragmentation spectra. An algorithm (ISIS: in silico identification software) and its implementation are presented and show great promise in generating in silico spectra of lipids for the purpose of structural identification. Instead of using chemical reaction rate equations or rules-based fragmentation libraries, the algorithm uses machine learning to find accurate bond cleavage rates in a mass spectrometer employing collision-induced dissociation tandem mass spectrometry. RESULTS: A preliminary test of the algorithm with 45 lipids from a subset of lipid classes shows both high sensitivity and specificity.

The role of a dipeptide outer-coordination sphere on H2-production catalysts: influence on catalytic rates and electron transfer.

The outer-coordination sphere of enzymes acts to fine-tune the active site reactivity and control catalytic rates, suggesting that incorporation of analogous structural elements into molecular catalysts may be necessary to achieve rates comparable to those observed in enzyme systems at low overpotentials. In this work, we evaluate the effect of an amino acid and dipeptide outer-coordination sphere on [Ni(P(Ph)(2)N(Ph-R)(2))(2)](2+) hydrogen production catalysts. A series of 12 new complexes containing non-natural amino acids or dipeptides was prepared to test the effects of positioning, size, polarity and aromaticity on catalytic activity. The non-natural amino acid was either 3-(meta- or para-aminophenyl)propionic acid terminated as an acid, an ester or an amide. Dipeptides consisted of one of the non-natural amino acids coupled to one of four amino acid esters: alanine, serine, phenylalanine or tyrosine. All of the catalysts are active for hydrogen production, with rates averaging ∼1000 s(-1), 40 % faster than the unmodified catalyst. Structure and polarity of the aliphatic or aromatic side chains of the C-terminal peptide do not strongly influence rates. However, the presence of an amide bond increases rates, suggesting a role for the amide in assisting catalysis. Overpotentials were lower with substituents at the N-phenyl meta position. This is consistent with slower electron transfer in the less compact, para-substituted complexes, as shown in digital simulations of catalyst cyclic voltammograms and computational modeling of the complexes. Combining the current results with insights from previous results, we propose a mechanism for the role of the amino acid and dipeptide based outer-coordination sphere in molecular hydrogen production catalysts.

The role of pendant amines in the breaking and forming of molecular hydrogen catalyzed by nickel complexes.

We present the results of a comprehensive theoretical investigation of the role of pendant amine ligands in the oxidation of H(2) and formation of H(2) by [Ni(P(R)(2)N(R')(2))(2)](2+) electrocatalysts (P(R)(2)N(R')(2) is the 1,5-R'-3,7-R derivative of 1,5-diaza-3,7-diphosphacyclooctane, in which R and R' are aryl or alkyl groups). We focus our analysis on the thermal steps of the catalytic cycle, as they are known to be rate-determining for both H(2) oxidation and production. We find that the presence of pendant amine functional groups greatly facilitates the heterolytic H(2) bond cleavage, resulting in a protonated amine and a Ni hydride. Only one single positioned pendant amine is required to serve this function. The pendant amine can also effectively shuttle protons to the active site, making the redistribution of protons and the H(2) evolution a very facile process. An important requirement for the overall catalytic process is the positioning of at least one amine in close proximity to the metal center. Indeed, only protonation of the pendant amines on the metal center side (endo position) leads to catalytically active intermediates, whereas protonation on the opposite side of the metal center (exo position) leads to a variety of isomers, which are detrimental to catalysis.

Analysis of the activation and heterolytic dissociation of H2 by frustrated Lewis pairs: NH3/BX3 (X = H, F, and Cl).

We performed a computational study of H(2) activation and heterolytic dissociation promoted by prototype Lewis acid/base pairs NH(3)/BX(3) (X = H, F, and Cl) to understand the mechanism in frustrated Lewis pairs (FLPs). Although the NH(3)/BX(3) pairs form strong dative bonds, electronic structure theories make it possible to explore the potential energy surface away from the dative complex, in regions relevant to H(2) activation in FLPs. A weakly bound precursor complex, H(3)N·H(2)·BX(3), was found in which the H(2) molecule interacts side-on with B and end-on with N. The BX(3) group is pyramidal in the case of X = H, similar to the geometry of BH(5), but planar in the complexes with X = F and Cl. The latter complexes convert to ion pairs, [NH(4)(+)][BHX(3)(-)] with enthalpy changes of 7.3 and -9.4 kcal/mol, respectively. The minimum energy paths between the FLP and the product ion pair of the chloro and fluoro complexes were calculated and analyzed in great detail. At the transition state (TS), the H(2) bond is weakened and the BX(3) moiety has undergone significant pyramidal distortion. As such, the FLP is prepared to accept the incipient proton and hydride ion on the product-side. The interaction energy of the H(2) with the acid/base pair and the different contributions for the precursor and TS complex from an energy decomposition analysis expose the dominant factors affecting the reactivity. We find that structural reorganization of the precursor complex plays a significant role in the activation and that charge-transfer interactions are the dominant stabilizing force in the activated complex. The electric field clearly has a role in polarizing H(2), but its contribution to the overall interaction energy is small compared to that from the overlap of the p(N), σ(H-H), σ*(H-H), and p(B) orbitals at the TS. Our detailed analysis of the interaction of H(2) with the FLP provides insight into the important components that should be taken into account when designing related systems to activate H(2).

About the barriers to reaction of CCl4 with HFeOH and FeCl2.

The reactions of zerovalent iron with water and carbon tetrachloride are of interest for environmental remediation of contaminated water and soil. Atom-dropping experiments have shown that the reactions of iron atoms with water and CCl(4) may produce HFeOH and FeCl(2), respectively, but these compounds are themselves unreactive toward CCl(4) at the low temperatures under which the atom-dropping experiments were performed. We report a modeling study of these reactions using density functional theory, ab initio Hartree-Fock and couple-cluster theory, and principles of Marcus-Hush theory to characterize the underlying intrinsic barriers and rationalize the experimental results. Electron-correlated CCSD(T) calculations (at B3LYP/TZVP optimized structures) show that the transition state for Cl atom transfer from CCl(4) to HFeOH arises from crossing of electronic states in which the configuration of Fe changes from a quintet high spin state in the Fe(II) reactant to a sextet high spin state in the Fe(III) products. The crossing point is 23.8 kcal/mol above a long-range precursor complex that is 2.1 kcal/mol more stable than the separated reactants. The electronic structure changes in these Cl atom transfer reactions involve unpairing of d electrons in Fe(II) and their recoupling with Cl-C σ bond electrons. These processes can be conveniently described by invoking the self-exchange reactions HFeOH/HFeClOH, FeCl(2)/FeCl(3), and CCl(4)/(•)CCl(3) for which we determined the energy barriers to be 15.5, 13.1, 18.6 kcal/mol, respectively. For the cross reaction FeCl(2)/CCl(4), we estimated a barrier of 16.6 kcal/mol relative to the separated reactants and 21.1 kcal/mol from the precursor complex. The magnitudes of the reaction barriers are consistent with reports of the absence of products in the atom-dropping experiments.

Understanding ion-ion interactions in bulk and aqueous interfaces using molecular simulations.

In addition to its scientific significance, the distribution of ions in the bulk and at aqueous interfaces is also very important for practical reasons. Providing a quantitative description of the ionic distribution, and describing interactions between ions in different environments, remains a challenge, and is the subject of current debate. In this study, we found that interionic potentials of mean force (PMFs) and interfacial properties are very sensitive to the ion-ion interaction potential models. Our study predicted a Sr(2+)--CI- PMF with no contact ion-pair state and a shallow solvent-separated ion-pair state. In addition, we were able to quantitatively capture the experimental X-ray reflectivity results of the aqueous salt interface of the Sr(2+)--Cl- ion-pair, and provided a detailed physical description of the interfacial structure for this system. We also predicted the Xray reflectivity results for SrBr2 and SrI2 systems.