Free Energy Of Proton Transfer Research Articles

Intramolecular proton transfer reaction dynamics using machine-learned ab initio potential energy surfaces

Hydrogen bonding interactions, which are central to various physicochemical processes, are investigated in the present study using ab initio-based machine learning potential energy surfaces. Abnormally strong intramolecular O–H⋯O hydrogen bonds, occurring in β-diketone enols of malonaldehyde and its derivatives, with substituents ranging from various electron-withdrawing to electron-donating functional groups, are studied. Machine learning force fields were constructed using a kernel-based force learning model employing ab initio molecular dynamics reference data. These models were used for molecular dynamics simulations at finite temperature, and dynamical properties were determined by computing proton transfer free-energy surfaces. The chemical systems studied here show progression toward barrier-less proton transfer events at an accuracy of correlated electronic structure methods. Markov state models of the conformational states indicate shorter intramolecular hydrogen bonds exhibiting higher proton transfer rates. We demonstrate how functional group substitution can modulate the strength of intramolecular hydrogen bonds by studying the thermodynamic and kinetic properties.

Proton transfer free energy and enthalpy from water to methanol

Proton transfer free energies and proton transfer enthalpies at the interface of different solvents are very important in chemistry and biology. In the present work, we present a general model to describe theoretically the proton transfer at the interface of two given solvents. The model is simple to apply, affordable and stable. It is based on first principles calculations of neutral and protonated clusters of the solvent molecules. The model is described and applied to the calculation of the water-methanol proton transfer free energy and enthalpy at standard conditions. We have thoroughly explored the potential energy surfaces (PESs) of neutral and protonated water clusters as well as neutral and protonated methanol clusters in the solvent phase. The located structures have been optimized at the MN15/6-31++G(d,p) level of theory. Using the favourable structures and the proposed model, the water-methanol proton transfer free energy and enthalpy are evaluated to be −6.1 kJ mol−1 and −13.3 kJ mol−1, respectively. The calculated water-methanol proton transfer enthalpy is found to be in excellent agreement with the experimental estimate of −15.9 kJ mol−1, based on the tetraphenylarsonium-tetraphenylborate (TATB) approach.

Water-ammonia and water-acetonitrile proton transfer free energy

Proton transfer at the interface of solvents are of great importance in chemistry and biology. Despite their importance, there are very rare computational models that do describe the proton transfer processes. In this work, we propose a simple and affordable yet efficient model to compute the proton transfer free energy and enthalpy. We applied the proposed model to the calculation of the water-ammonia as well as water-acetonitrile proton transfer free energy and enthalpy. To compute the water-ammonia proton transfer free energy and enthalpy within this model, we need the structures of neutral and protonated water clusters as well as the structures of neutral and protonated ammonia clusters optimized in the solvent phases. Thus we started by exploring the potential energy surfaces (PESs) to locate the most stable structures of the clusters involved in the model. We initially generated the geometries using the ABCluster code followed by full optimization at the MN15/6–31++G(d,p) level of theory combined with the polarized continuum model. As a result, we have reported the global minima energy structures of the investigated clusters in the solvent phase. At room temperature, the water-ammonia (respectively water-acetonitrile) proton transfer free energy and enthalpy are evaluated to be −109.9 and −104.2 kJ mol−1 (respectively 60.2 and 58.0 kJ mol−1), respectively. The calculated water-ammonia as well as water-acetonitrile proton transfer free energy and enthalpy are found to be in good agreement with experimental values when available.

Free energy of proton transfer at the water-TiO2 interface from ab initio deep potential molecular dynamics.

TiO2 is a widely used photocatalyst in science and technology and its interface with water is important in fields ranging from geochemistry to biomedicine. Yet, it is still unclear whether water adsorbs in molecular or dissociated form on TiO2 even for the case of well-defined crystalline surfaces. To address this issue, we simulated the TiO2–water interface using molecular dynamics with an ab initio-based deep neural network potential. Our simulations show a dynamical equilibrium of molecular and dissociative adsorption of water on TiO2. Water dissociates through a solvent-assisted concerted proton transfer to form a pair of short-lived hydroxyl groups on the TiO2 surface. Molecular adsorption of water is ΔF = 8.0 ± 0.9 kJ mol−1 lower in free energy than the dissociative adsorption, giving rise to a 5.6 ± 0.5% equilibrium water dissociation fraction at room temperature. Due to the relevance of surface hydroxyl groups to the surface chemistry of TiO2, our model might be key to understanding phenomena ranging from surface functionalization to photocatalytic mechanisms.

Conformational sampling and polarization of Asp26 in pKa calculations of thioredoxin.

Thioredoxin is a protein that has been used as model system by various computational methods to predict the pKa of aspartate residue Asp26 which is 3.5 units higher than a solvent exposed one (eg, Asp20). Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation, the Gibbs free energy of proton transfer between Asp26 and Asp20, which is fully solvated in a loop region of the protein, is calculated with the Amber99sb force field in alchemical transformations. The varying polarization of the two residues in different molecular environments and protonation states is described by Hirshfeld-I (HI) atomic charges obtained from the averaged polarized electron density. Our results show that the Gibbs free energy of proton transfer is dependent on the protein conformation, the proper sampling of the neighboring Lys57 residue orientations and on water molecules entering the hydrophobic cavity upon deprotonating Asp26. The inclusion of the polarization of both aspartate residues in the free energy cycle by HI atomic charges corrects the results from the non-polarizable force field and reproduces the experimental ΔpKa value of Asp26.

Excited-State Proton Transfer of 5,8-Dicyano-2-naphthol in High-Temperature and High-Pressure Methanol: Effect of Solvent Polarity and Hydrogen Bonding Ability.

Excited-state proton transfer (ESPT) of 5,8-dicyano-2-naphthol (DCN2) in methanol at 30 MPa isobar between 294 and 543 K was studied using time-resolved fluorescence spectroscopy. From room temperature up to 513 K, a fluorescence band from an anionic form (RO-*, a proton dissociated form of DCN2) was observed, which indicates that the ESPT occurred under these thermal conditions. The time profiles of fluorescence intensity of the normal form of DCN2 (ROH*) (proton-associated form of DCN2) and RO-* were analyzed, considering the diffusion process of the contact ion pair RO-*···H in the Coulomb field based on the Debye-Smoluchowski theory. Proton dissociation rate was slower than the solvent reorganization rate estimated from the dynamic Stokes shift, indicating that the proton transfer (PT) is not influenced by the solvent dynamic factor but by the solvation free energy. The proton dissociation rate constants were discussed from the change of the activation free energy of PT controlled by the solvent characteristics. It was found that the PT dissociation rate constants for various alcohols under different thermal conditions could be explained by the competing effects of hydrogen bonding and dipolarity/polarizability that controlled the energy state of ROH* and RO-*···H, respectively.

Role of Protein Dynamics in Allosteric Control of the Catalytic Phosphoryl Transfer of Insulin Receptor Kinase.

The catalytic and allosteric mechanisms of insulin receptor kinase (IRK) are investigated by a combination of ab initio and semiempirical quantum mechanical and molecular mechanical (QM/MM) methods and classical molecular dynamics (MD) simulations. The simulations reveal that the catalytic reaction proceeds in two steps, starting with the transfer of a proton from substrate Tyr to the catalytic Asp1132, followed by the phosphoryl transfer from ATP to substrate Tyr. The enhancement of the catalytic rate of IRK upon phosphorylations in the enzyme's activation loop is found to occur mainly via changes to the free energy landscape of the proton transfer step, favoring the proton transfer in the fully phosphorylated enzyme. In contrast, the effects of the phosphorylations on the phosphoryl transfer are smaller. Equilibrium MD simulations show that IRK phosphorylations affect the protein dynamics of the enzyme before the proton transfer to Asp1132 with only a minor effect after the proton transfer. This finding is consistent with the large change in the proton transfer free energy and the smaller change in the free energy barrier of phosphoryl transfer found by QM/MM simulations. Taken together, the present results provide details on how IRK phosphorylation exerts allosteric control of the catalytic activity via modifications of protein dynamics and free energy landscape of catalytic reaction. The results also highlight the importance of protein dynamics in connecting protein allostery and catalysis to control catalytic activity of enzymes.

Reinvestigation of spectroscopic properties for ammonia–hydrogen halide complexes from Car–Parrinello Molecular Dynamics

Infrared spectra of ammonia–hydrogen chloride and hydrogen bromide were obtained from Car–Parrinello Molecular Dynamics simulations. Proton distribution and proton transfer free energy along hydrogen bond together with hydrogen bond angle distribution during the simulations have been calculated. VPT2 and VSCF anharmonic vibrational frequencies have been also computed at DFT (BLYP) and post-Hartree–Fock (MP2) levels. Hydrogen bond properties obtained from MD simulations show good agreement with previously reported static results. In the absence of experimental gas phase infrared spectra, reported results shed further light on the spectroscopic properties of ammonia–hydrogen halides molecular complexes.

Chemical rescue of enzymes: proton transfer in mutants of human carbonic anhydrase II.

In human carbonic anhydrase II (HCA II), the mutation of position 64 from histidine to alanine (H64A) disrupts the rate limiting proton transfer (PT) event, resulting in a reduction of the catalytic activity of the enzyme as compared to the wild-type. Potential of mean force (PMF) calculations utilizing the multistate empirical valence bond (MS-EVB) methodology for H64A HCA II yields a PT free energy barrier significantly higher than that found in the wild-type enzyme. This high barrier, determined in the absence of exogenous buffer and assuming no additional ionizable residues in the PT pathway, indicates the likelihood of alternate enzyme pathways that utilize either ionizable enzyme residues (self-rescue) and/or exogenous buffers (chemical rescue). It has been shown experimentally that the catalytic activity of H64A HCA II can be chemically rescued to near wild-type levels by the addition of the exogenous buffer 4-methylimidazole (4MI). Crystallographic studies have identified two 4MI binding sites, yet site-specific mutations intended to disrupt 4MI binding have demonstrated these sites to be nonproductive. In the present work, MS-EVB simulations show that binding of 4MI near Thr199 in the H64A HCA II mutant, a binding site determined by NMR spectroscopy, results in a viable chemical rescue pathway. Additional viable rescue pathways are also identified where 4MI acts as a proton transport intermediary from the active site to ionizable residues on the rim of the active site, revealing a probable mode of action for the chemical rescue pathway.

Calculation of the Free Energy of Proton Transfer from an Aqueous Phase to Liquid Acetonitrile

Protons in liquid phases are stabilized by long-range electrostatic interactions, hydrogen bonding, and the formation of covalent bonds between H+ and solvent molecules. Thus, a small proton affinity, a low dielectric constant, or the inability to form hydrogen bonds that characterize many nonaqueous solvents hinders the transfer of protons from an aqueous phase. As a result, the particle that is readily transferred is a hydrated proton, H2n+1On+, rather than the bare proton, H+. Here we present calculations of the free energy of proton transfer from water to liquid acetonitrile, including the dehydrated particle, H+, and two hydrated particles, H3O+ and H9O4+. We use a combination of ab initio density functional theory and a polarizable continuum model within the self-consistent reaction field method. This allows the first and second solvation shells of the proton to be described explicitly from first principles. Vibrational contributions to the enthalpy and entropy have been added in. Values taken from ...

Polyelectrolyte Titrations. The System Na +-H + on Carboxymethyldextran

From acid-base titrations of carboxymethyldextran (HP) the equilibrium "constant" for the reaction H + (aq) + P - rlhar2; HP (K) has been computed. This quantity varies with the degree of dissociation, α, indicating nonideal behavior. The data have been fitted to a three-parameter model, which takes nonideality into account. The model gives a satisfactory fit to data pH(v). Moreover, the three-parameter model offers an estimate of the intrinsic protonation constant, giving log K int = 3.39 ∓ 0.03. The data also permit an estimate of the equilibrium constant for the reaction H + (aq) rlhar2; H + (CmDx); i.e., the free energy of proton transfer at infinite dilution from the aqueous phase to the polyelectrolyte at infinite solution giving δG = -4.67 kJ.

Stability of "salt bridges" in membrane proteins.

We estimate the free energies of transfer of ionized amino acid side chains in water to both their ion-paired and neutral hydrogen-bonded states in low-dielectric media. The difference between the two free energies corresponds to the proton transfer free energy in a "salt bridge" formed between acidic and basic groups (i.e., lysine and glutamic acid residues). Our approach is to use gas phase proton transfer data, pK values, and experimentally determined solvation energies to estimate the standard state free energy changes involved in transferring amino acid side chains, in both ionized and neutral form, from water (dielectric constant epsilon = 80) to vacuum (epsilon = 1). The familiar expressions for the charging energy of a sphere and dipole are used to interpolate between epsilon = 1 and epsilon = 80. Our results suggest that it costs approximately 10-16 kcal/mol to transfer a salt bridge from water to a medium of epsilon = 2-4, in ionized or neutral form within the resolution of our estimates. The proton transfer energy is thus approximately 0. The tendency of salt bridges to form additional hydrogen bonds in real proteins suggests that the ion pair will be present in most biological systems.