Re: Watts et al. Proteins 2002;48:161-168.
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Alcohol Oxidoreductases↗
Biomedical subjects
Hugh B Nicholas
Publications and source records attributed to Hugh B Nicholas.
An algorithm for identification and ranking of family-specific residues, applied to the ALDH3 family.
An algorithm for detecting amino acid residues characteristic of individual protein families from within aligned collections of paralogous sequences, and its application to the ALDH3 family versus the rest of the ALDH extended family is described. Residues illuminated by this analysis include a key intramolecular tether, a lysine that makes an intersubunit contact at the dimer interface, three residues in close association with the substrate-binding funnel, and a pair of residues suggested to participate in proton relay during the catalytic cycle.
Aldehyde Dehydrogenase↗
Initial catalytic events in class 3 aldehyde dehydrogenase: MM and QM/MM simulations.
A novel enzyme mechanism has been predicted by computer simulations for formation of the thiohemiacetal intermediate in the rat ALDH3A1 enzyme. We used molecular mechanics simulations to study the atomic details of substrate binding and quantum mechanical/molecular mechanical methods to study the Cys-243 thiolate attack on benzaldehyde (BA) substrate. BA was found to produce more reactive conformers when aligned for formation of the tetrahedral thiohemiacetal in the R-configuration. In addition, the sulfhydryl proton was seen to be important for initial binding of the substrate. Finally, the free energy differences between forming a thiohemiacetal oxyanion intermediate versus forming a neutral thiohemiacetal intermediate where a proton is donated to the intermediate from the surroundings strongly favor the latter. Our results suggest that the proton donor is the amide proton from the Cys-243 backbone supported by interactions with Lys-235.
Aldehyde Dehydrogenase↗
Prediction of tyrosine sulfation in seven-transmembrane peptide receptors.
Posttranslational modification by tyrosine sulfation regulates many important protein protein interactions and modulates the binding affinity and specificity of seventransmembrane peptide receptors. We developed a log-odds position-specific-scoring-matrix (PSSM) to accurately predict tyrosine sulfation using 62 tyrosine sites known to be sulfated and 421 tyrosine sites known not to be sulfated. We predict that 49 tyrosines of 32 seven-transmembrane peptide receptors are sulfated. Although we did not incorporate characteristics of confirmed sulfation sites such as clustering and conservation across species into our PSSM, our predicted sites nevertheless exhibited these characteristics. The observed conservation suggests that there are strong evolutionary pressures to preserve selected biological activity of seven-transmembrane receptors. The predicted tyrosine sulfation sites predominantly occur in the extracellular tail and extracellular loop 2, regions consistent with their association with binding pockets of the receptor.
Amino Acid Sequence↗
Strategies for multiple sequence alignment.
We present an overview of multiple sequence alignments to outline the practical consequences for the choices among different techniques and parameters. We begin with a discussion of the scoring methods for quantifying the quality of a multiple sequence alignment, followed by a discussion of the algorithms implemented within a variety of multiple sequence alignment programs. We also discuss additional alignment details such as gap penalty and distance metrics. The paper concludes with a discussion on how to improve alignment quality and the limitations of the techniques described in this paper
Algorithms↗