Richard Wolfenden

Bio: Richard Wolfenden is an academic researcher from University of North Carolina at Chapel Hill. The author has contributed to research in topics: Transition state analog & Cytidine deaminase. The author has an hindex of 56, co-authored 198 publications receiving 13323 citations. Previous affiliations of Richard Wolfenden include University of Wisconsin-Madison & University of Oxford.

Affinities of Amino Acid Side Chains for Solvent Water

Abstract: Equilibria of distribution of amino acid side chains, between their dilute aqueous solutions and the vapor phase at 25 degrees C, have been determined by dynamic vapor pressure measurements. After correction to pH 7, the resulting scale of "hydration potentials", or free energies of transfer from the vapor phase to neutral aqueous solution, spans a range of approximately 22 kcal/mol. The side chain of arginine is much more hydrophilic than those of the other common amino acids, with an equilibrium constant of approximately 10(15) for transfer from the vapor phase to neutral aqueous solution. Hydration potentials are more closely correlated with the relative tendencies of the various amino acids to appear at the surface of globular proteins than had been evident from earlier distribution studies on the free amino acids. Both properties are associated with a pronounced bias in the genetic code.

A proficient enzyme

Abstract: Orotic acid is decarboxylated with a half-time (t1/2) of 78 million years in neutral aqueous solution at room temperature, as indicated by reactions in quartz tubes at elevated temperatures. Spontaneous hydrolysis of phosphodiester bonds, such as those present in the backbone of DNA, proceeds even more slowly at high temperatures, but the heat of activation is less positive, so that dimethyl phosphate is hydrolyzed with a t1/2 of 130,000 years in neutral solution at room temperature. These values extend the known range of spontaneous rate constants for reactions that are also susceptible to catalysis by enzymes to more than 14 orders of magnitude. Values of the second-order rate constant kcat/Km for the corresponding enzyme reactions are confined to a range of only 600-fold, in contrast. Orotidine 59-phosphate decarboxylase, an extremely proficient enzyme, enhances the rate of reaction by a factor of 10(17) and is estimated to bind the altered substrate in the transition state with a dissociation constant of less than 5 x 10(-24) M.

The depth of chemical time and the power of enzymes as catalysts.

Abstract: The fastest known reactions include reactions catalyzed by enzymes, but the rate enhancements that enzymes produce had not been fully appreciated until recently. In the absence of enzymes, these same reactions are among the slowest that have ever been measured, some with half-times approaching the age of the Earth. This difference provides a measure of the proficiencies of enzymes as catalysts and their relative susceptibilities to inhibition by transition-state analogue inhibitors. Thermodynamic comparisons between spontaneous and enzyme-catalyzed reactions, coupled with structural information, suggest that in addition to electrostatic and H-bonding interactions, the liberation of water molecules from an enzyme's active site into bulk solvent sometimes plays a prominent role in determining the relative binding affinities of the altered substrate in the ground state and transition state. These comparisons also indicate a high level of synergism in the action of binding determinants of both the substrate a...

Comparing the polarities of the amino acids: side-chain distribution coefficients between the vapor phase, cyclohexane, 1-octanol, and neutral aqueous solution

Abstract: To obtain an indication of the tendencies of amino acids to leave water and enter a truly nonpolar condensed phase, distribution coefficients between dilute solution in water and dilute solution in wet cy- clohexane have been determined for each of the common amino acid side chains at pH 7; they are found to be closely related to the inside-outside distributions of the side chains observed in globular proteins. There was no evidence that excess water enters cyclohexane in association with these solutes. Cyclohexane-to-water distribution coefficients can be combined with vapor-to-water distribution coefficients reported earlier to yield vapor-to-cyclohexane distribution coefficients. Vapor-to-cyclohexane distribution coefficients provide an experimental index of susceptibility to attraction by dispersion forces, and the corresponding free energies are found to be linearly related to side-chain surface areas. Observations using different solvents and variously substituted side chains suggest that alcohols such as 1-octanol exert a specific attraction on the side chain of tryptophan. When less polar phases are used as a reference, leucine, isoleucine, valine, phenylalanine, and methionine are found to be more hydrophobic than tryptophan.

Quantum mechanical continuum solvation models.

Abstract: 6.2.2. Definition of Effective Properties 3064 6.3. Response Properties to Magnetic Fields 3066 6.3.1. Nuclear Shielding 3066 6.3.2. Indirect Spin−Spin Coupling 3067 6.3.3. EPR Parameters 3068 6.4. Properties of Chiral Systems 3069 6.4.1. Electronic Circular Dichroism (ECD) 3069 6.4.2. Optical Rotation (OR) 3069 6.4.3. VCD and VROA 3070 7. Continuum and Discrete Models 3071 7.1. Continuum Methods within MD and MC Simulations 3072

CHARMM: the biomolecular simulation program.

Abstract: CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecu- lar simulation program. It has been developed over the last three decades with a primary focus on molecules of bio- logical interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estima- tors, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numer- ous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.

The MARTINI force field : Coarse grained model for biomolecular simulations

Abstract: We present an improved and extended version of our coarse grained lipid model. The new version, coined the MARTINI force field, is parametrized in a systematic way, based on the reproduction of partitioning free energies between polar and apolar phases of a large number of chemical compounds. To reproduce the free energies of these chemical building blocks, the number of possible interaction levels of the coarse-grained sites has increased compared to those of the previous model. Application of the new model to lipid bilayers shows an improved behavior in terms of the stress profile across the bilayer and the tendency to form pores. An extension of the force field now also allows the simulation of planar (ring) compounds, including sterols. Application to a bilayer/cholesterol system at various concentrations shows the typical cholesterol condensation effect similar to that observed in all atom representations.

Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis

Abstract: The protease responsible for the cleavage of poly(ADP-ribose) polymerase and necessary for apoptosis has been purified and characterized. This enzyme, named apopain, is composed of two subunits of relative molecular mass (M(r)) 17K and 12K that are derived from a common proenzyme identified as CPP32. This proenzyme is related to interleukin-1 beta-converting enzyme (ICE) and CED-3, the product of a gene required for programmed cell death in Caenorhabditis elegans. A potent peptide aldehyde inhibitor has been developed and shown to prevent apoptotic events in vitro, suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.