Dudley H. Williams

Bio: Dudley H. Williams is an academic researcher from University of Cambridge. The author has contributed to research in topics: Mass spectrometry & Mass spectrum. The author has an hindex of 73, co-authored 587 publications receiving 21776 citations. Previous affiliations of Dudley H. Williams include University of Edinburgh.

Spectroscopic methods in organic chemistry

Abstract: Ultraviolet and Visible Spectra. Infrared Spectra. Nuclear Magnetic Resonance Spectra. Mass Spectra. Structure Elucidation by Joint Application of UV

Understanding noncovalent interactions: ligand binding energy and catalytic efficiency from ligand-induced reductions in motion within receptors and enzymes.

Abstract: Noncovalent interactions are sometimes treated as additive and this enables useful average binding energies for common interactions in aqueous solution to be derived. However, the additive approach is often not applicable, since noncovalent interactions are often either mutually reinforcing (positively cooperative) or mutually weakening (negatively cooperative). Ligand binding energy is derived (positively cooperative binding) when a ligand reduces motion within a receptor. Similarly, transition-state binding energy is derived in enzyme-catalyzed reactions when the substrate transition state reduces the motions within an enzyme. Ligands and substrates can in this way improve their affinities for these proteins. The further organization occurs with a benefit in bonding (enthalpy) and a limitation in dynamics (cost in entropy), but does not demand the making of new noncovalent interactions, simply the strengthening of existing ones. Negative cooperativity induces converse effects: less efficient packing, a cost in enthalpy, and a benefit in entropy.

Identification of 1,25-Dihydroxycholecalciferol, a New Kidney Hormone controlling Calcium Metabolism

Abstract: A vitamin D metabolite, 25-dihydroxycholecalciferol, is further hydroxylated by kidney before acting as a hormone on target tissues. The structure of this kidney metabolite is now described.

The Vancomycin Group of Antibiotics and the Fight against Resistant Bacteria.

Abstract: This review is an account of the discoveries in the Cambridge group of the structures and mode of action of the glycopeptide antibiotics of the vancomycin group. These antibiotics are now of enormous clinical importance, for among their members are two (vancomycin and teicoplanin) of the three antibiotics of last resort against resistant bacterial pathogens (particularly methicillin-resistant Staphylococcus aureus (MRSA, or “superbugs”)) in our hospitals, which would otherwise often be lethal. Their combined sales are of the order of US$1 billion per annum. The structure determination in our laboratory started just over 25 years ago. Within ten years the first glycopeptide structures had been determined. This was quickly followed by the determination of the molecular basis of their action, through the making of five hydrogen bonds to a cell wall peptide precursor that terminated in -Lys-d-Ala-d-Ala. In the early 1990s, we established that all the glycopeptides so far examined (other than teicoplanin) form dimers, and shortly after showed that dimerization promotes antibiotic activity. Concurrently, we were able to demonstrate that teicoplanin possesses a membrane anchor that can act to promote antibiotic activity in lieu of dimerization. The devices of dimerization and membrane anchoring, when acting concurrently, appear to be able to account at least in part for the remarkable activity of a new semi-synthetic glycopeptide—developed at Eli Lilly—against bacteria that are resistant even to vancomycin. A full understanding of these devices is important, since occurrences of the “nightmare scenario” that clinicians have feared over recent years—that resistance to vancomycin will appear in new forms of MRSA—have recently been reported.

Why are secondary metabolites (natural products) biosynthesized

Abstract: We adopt the definition of a natural product as a substance that has no known role in the internal economy of the producing organism. The literature abounds with conflicting views for the existence of such natural products. We propose that all such structures serve the producing organisms by improving their survival fitness. We argue that this conclusion is necessitated by the fact that natural products are normally complex structures, whose biosynthesis is programmed by many kilobases of DNA. If it were otherwise, the pressures of Darwinian natural selection would have precluded the expenditure of so much metabolic energy in their construction and the development of such complexity. We further conclude that a natural product improves the producer's survival fitness by acting at specific receptors in competing organisms. Current studies of natural products interacting with receptors support this view, in terms of both the sophistication of the molecule/molecule recognition and the mechanistic details of physiological action. By the application of Occam's razor and general weaknesses of other hypotheses, these other hypotheses are rejected. It is a consequence of our proposal that natural product/receptor interactions of sophistication comparable to enzyme/substrate interactions will be commonplace. Additionally, structures that are candidates to interact with known receptors (e.g., double helical DNA) can on occasion be suggested by inspection of the structures. A range of evidence to support the general conclusions is presented.

Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

Abstract: A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .

Probability-based protein identification by searching sequence databases using mass spectrometry data.

Abstract: Several algorithms have been described in the literature for protein identification by searching a sequence database using mass spectrometry data. In some approaches, the experimental data are peptide molecular weights from the digestion of a protein by an enzyme. Other approaches use tandem mass spectrometry (MS/MS) data from one or more peptides. Still others combine mass data with amino acid sequence data. We present results from a new computer program, Mascot, which integrates all three types of search. The scoring algorithm is probability based, which has a number of advantages: (i) A simple rule can be used to judge whether a result is significant or not. This is particularly useful in guarding against false positives. (ii) Scores can be compared with those from other types of search, such as sequence homology. (iii) Search parameters can be readily optimised by iteration. The strengths and limitations of probability-based scoring are discussed, particularly in the context of high throughput, fully automated protein identification.

ReaxFF: A Reactive Force Field for Hydrocarbons

Abstract: To make practical the molecular dynamics simulation of large scale reactive chemical systems (1000s of atoms), we developed ReaxFF, a force field for reactive systems. ReaxFF uses a general relationship between bond distance and bond order on one hand and between bond order and bond energy on the other hand that leads to proper dissociation of bonds to separated atoms. Other valence terms present in the force field (angle and torsion) are defined in terms of the same bond orders so that all these terms go to zero smoothly as bonds break. In addition, ReaxFF has Coulomb and Morse (van der Waals) potentials to describe nonbond interactions between all atoms (no exclusions). These nonbond interactions are shielded at short range so that the Coulomb and van der Waals interactions become constant as Rij → 0. We report here the ReaxFF for hydrocarbons. The parameters were derived from quantum chemical calculations on bond dissociation and reactions of small molecules plus heat of formation and geometry data for...

Hydrophobic, Highly Conductive Ambient-Temperature Molten Salts

Abstract: New, hydrophobic ionic liquids with low melting points (<−30 °C to ambient temperature) have been synthesized and investigated, based on 1,3-dialkyl imidazolium cations and hydrophobic anions. Other imidazolium molten salts with hydrophilic anions and thus water-soluble are also described. The molten salts were characterized by NMR and elemental analysis. Their density, melting point, viscosity, conductivity, refractive index, electrochemical window, thermal stability, and miscibility with water and organic solvents were determined. The influence of the alkyl substituents in 1, 2, 3, and 4(5)-positions on these properties was scrutinized. Viscosities as low as 35 cP (for 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)amide (bis(triflyl)amide) and trifluoroacetate) and conductivities as high as 9.6 mS/cm were obtained. Photophysical probe studies were carried out to establish more precisely the solvent properties of 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)amide). The hydrophobi...

The dilemma of plants: To grow or defend.

Abstract: Physiological and ecological constraints play key roles in the evolution of plant growth patterns, especially in relation to defenses against herbivores. Phenotypic and life history theories are unified within the growth-differentiation balance (GDB) framework, forming an integrated system of theories explaining and predicting patterns of plant defense and competitive interactions in ecological and evolutionary time. Plant activity at the cellular level can be classified as growth (cell division and enlargement) of differentiation (chemical and morphological changes leading to cell maturation and specialization). The GDB hypothesis of plant defense is premised upon a physiological trade-off between growth and differentiation processes. The trade-off between growth and defense exists because secondary metabolism and structural reinforcement are physiologically constrained in dividing and enlarging cells, and because they divert resources from the production of new leaf area. Hence the dilemma of plants: Th...