Redox potentials and acidity constants from density functional theory based molecular dynamics.

CONSPECTUS: All-atom methods treat solute and solvent at the same level of electronic structure theory and statistical mechanics. All-atom computation of acidity constants (pKa) and redox potentials is still a challenge. In this Account, we review such a method combining density functional theory based molecular dynamics (DFTMD) and free energy perturbation (FEP) methods. The key computational tool is a FEP based method for reversible insertion of a proton or electron in a periodic DFTMD model system. The free energy of insertion (work function) is computed by thermodynamic integration of vertical energy gaps obtained from total energy differences. The problem of the loss of a physical reference for ionization energies under periodic boundary conditions is solved by comparing with the proton work function computed for the same supercell. The scheme acts as a computational hydrogen electrode, and the DFTMD redox energies can be directly compared with experimental redox potentials. Consistent with the closed shell nature of acid dissociation, pKa estimates computed using the proton insertion/removal scheme are found to be significantly more accurate than the redox potential calculations. This enables us to separate the DFT error from other sources of uncertainty such as finite system size and sampling errors. Drawing an analogy with charged defects in solids, we trace the error in redox potentials back to underestimation of the energy gap of the extended states of the solvent. Accordingly the improvement in the redox potential as calculated by hybrid functionals is explained as a consequence of the opening up of the bandgap by the Hartree-Fock exchange component in hybrids. Test calculations for a number of small inorganic and organic molecules show that the hybrid functional implementation of our method can reproduce acidity constants with an uncertainty of 1-2 pKa units (0.1 eV). The error for redox potentials is in the order of 0.2 V.J. C. thanks Emmanuel College at Cambridge for research fellowship. Dr. Aron Cohen is ackowledged for helpful discussions about density functionals and the delocalization er- ror. X.-D. L. thanks National Science Foundation of China (Nos. 41273074 and 41222015), the Foundation for the Author of National Excellent Doctoral Dissertation of PR China (No. 201228) and Newton International Fellow Program for nancial support. We thank HECToR and UKCP consortium for computing time.This is the accepted manuscript. It will be embargoed until 12 months after publication by ACS. The final version is available from http://pubs.acs.org/doi/abs/10.1021/ar500268

The rational of catalytic activity of herpes simplex virus thymidine kinase. a combined biochemical and quantum chemical study.

Most antiherpes therapies exploit the large substrate acceptance of herpes simplex virus type 1 thymidine kinase (TK(HSV1)) relative to the human isoenzyme. The enzyme selectively phosphorylates nucleoside analogs that can either inhibit viral DNA polymerase or cause toxic effects when incorporated into viral DNA. To relate structural properties of TK(HSV1) ligands to their chemical reactivity we have carried out ab initio quantum chemistry calculations within the density functional theory framework in combination with biochemical studies. Calculations have focused on a set of ligands carrying a representative set of the large spectrum of sugar-mimicking moieties and for which structural information of the TK(HSV1)-ligand complex is available. The k(cat) values of these ligands have been measured under the same experimental conditions using an UV spectrophotometric assay. The calculations point to the crucial role of electric dipole moment of ligands and its interaction with the negatively charged residue Glu(225). A striking correlation is found between the energetics associated with this interaction and the k(cat) values measured under homogeneous conditions. This finding uncovers a fundamental aspect of the mechanism governing substrate diversity and catalytic turnover and thus represents a significant step toward the rational design of novel and powerful prodrugs for antiviral and TK(HSV1)-linked suicide gene therapies

Trimesic acid on Cu in ethanol: Potential-dependent transition from 2-D adsorbate to 3-D metal-organic framework

We report the potential-dependent interactions of trimesic acid with Cu surfaces in EtOH. CV experiments and electrochemical surface-enhanced Raman spectroscopy show the presence of an adsorbed trimesic acid layer on Cu at potentials lower than 0 V vs Cu. The BTC coverage increases as the potential increases, reaching a maximum at 0 V. Based on molecular dynamics simulations, we report adsorption geometries and possible structures of the organic adlayer. We find that, depending on the crystal facet, trimesic acid adsorbs either flat or with one or two of the carboxyl groups facing the metal surface. At higher coverages, a multi-layer forms that is composed mostly of flat-lying trimesic acid molecules. Increasing the potential beyond 0 V activates the Cu-adsorbate interface in such a way that under oxidation of Cu to Cu2 +, a 3-D metal-organic framework forms directly on the electrode surface.PS gratefully acknowledges the Max Planck Graduate Center and the Studienstiftung des deutschen Volkes for the funding. KFD gratefully acknowledges the generous funding through the Emmy Noether program of the Deutsche Forschungsgemeinschaft (DO 1691/1-1)

Ab initio studies of targets for pharmaceutical intervention

In this thesis we further explore the capability of first principle methods to provide insights on drug/target interactions in different contexts. In the first part of this work, we address the issue whether OFT methods can be used as a potential tool for drug-screening. First principle calculations are particularly interesting for screening the energetics of drug/target interactions, as they do not involve the painstaking procedure of developing each set of new parameters for each novel drug. In this context, we use ab initio_ methods as a novel tool to determine a scoring function in a series of prodrug I target (herpes simplex type 1 thyimidine kinase) complexes for gene-therapy based anticancer approaches. This work, accompanied by experimental data provided by Prof. Folkers' Lab (ETH, Zurich) provides a new, very simple, ab initiobased approach to the construction of scoring functions for drug-screening. In the second part of the thesis we investigate the capability of OFT to describe non trivial interactions which are encountered in several inhibitor/enzyme complexes of pharmaceutical interest. Clearly, the description of these non-trivial phenomena might require the use of electronic structure methods. Here we present an example of cation-n interaction found in the human immunodeficiency virus reverse transcriptase (HIV-1 RT), one of the major targets for anti-AIDS therapy(Furman et al., 2000)). Furthermore, we provide a description of the hydroxyl-n interactions in the active site of \u3bc-glutathione S-transferase(Xiao et al., 1996) (\u3bc-GST), whose differential expression has been implicated in the development of cancers as well as their resistance to chemotherapeutic drugs ((Mccallum et al., 2000) and reference therein). Finally we present a classic problem treated by quantum-chemical methods: the simulation of an enzymatic reaction. We focus on a class of cysteine proteases, the caspases. These enzymes are extremely important targets for pharmaceutical intervention in therapies against Alzheimer's and other neurodegenerative processes, yet very few inhibitors have been so far designed. Since an important class of inhibitors is the given by the transition state analogs, it is of importance to fully understand the \ub7 enzymatic reaction, that is the hydrolysis of peptides. Because of the crucial importance of temperature and environment(Karplus, 2000; Glennon and Warshel, 1998; Varnai and Warshel, 2000; Villa et al., 2000) effects for enzymatic catalysis, we use here a hybrid Car-Parrinello Molecular dynamics I Molecular mechanics approach recently developed in the Lab of Prof. U. Roethlisberger (Laio et al., 2001 ). This technique allows to evaluate the intermolecular interactions at the active site from electronic structure calculations as the simulation proceeds(Car and Parrinello, 1985). Steric and electrostatic effects of the protein scaffold on the quantum region are included using classical MD approach on the rest of the system. The free energy of the process is calculated using a thermodynamic integration approach(Ciccotti et al., 1989; Carloni et al., 2000; Piana et al., 2001). This thesis is organized as follows. The first chapter provides a description of the used computational techniques. The following chapter describes the systems investigated here and summarizes our findings. The subsequent three chapters are devoted to a - detailed description of my thesis work. In a final chapter we draw some conclusions and provide a perspective for possible future applications, which could follow this work

Electron Transfer Properties from Atomistic Simulations and Density Functional Theory

Marcus theory of electron transfer is the quintessential example of a successful theory in physical chemistry. In this paper, we describe the theoretical approach we have adopted to compute key parameters in Marcus theory. In our method, based on molecular dynamics simulations and density functional theory, the redox center and its environment are treated at the same level of theory. Such a detailed atomistic model describes specific solvent–solute interactions, such as hydrogen bonding, explicitly. The quantum chemical nature of our computations enables us to study the effect of chemical modifications of the redox centers and deals accurately with the electronic polarization of the environment. Based on results of previous work, we will illustrate that quantitative agreement with experiment can be obtained for differences in redox potentials and solvent reorganization energies for systems ranging from small organic compounds to proteins in solution

Sum Frequency Generation Spectra from Velocity–Velocity Correlation Functions

We developed an expression for the calculation of the sum frequency generation spectra (SFG) of water interfaces that is based on the projection of the atomic velocities on the local normal modes. Our approach permits one to obtain the SFG signal from suitable velocity–velocity correlation functions, reducing the computational cost to that of the accumulation of a molecular dynamics trajectory, and therefore cutting the overhead costs associated with the explicit calculation of the dipole moment and polarizability tensor. Our method permits to interpret the peaks in the spectrum in terms of local modes, also including the bending region. The results for the water–air interface, obtained using <i>ab initio</i> molecular dynamics simulations, are discussed in connection to recent phase resolved experimental data