Papers by Richard Sessions
Proceedings of the National Academy of Sciences, 2010
Journal of Chemical Information and Modeling, 2014
Many structurally and therapeutically diverse drugs interact with the human heart K+ channel hERG... more Many structurally and therapeutically diverse drugs interact with the human heart K+ channel hERG by binding within the K+ permeation pathway of the open channel, leading to drug-induced 'long QT syndrome'. Drug binding to hERG is often stabilized by inactivation gating. In the absence of a crystal structure, hERG pore homology models have been used to characterize drug interactions. Here we assess potentially inactivated states of the bacterial K+ channel, KcsA, as templates for inactivated state hERG pore models in the context of drug binding using computational docking. Although Flexidock and GOLD docking produced low energy score poses in the models tested, each method selected a MthK K+ channel-based model over models based on the putative inactivated state KcsA structures for each of the 9 drugs tested. The variety of docking poses found indicates that an optimal arrangement for drug binding of aromatic side chains in the hERG pore can be achieved in several different configurations. This plasticity of the drug "binding site" is likely to be a feature of the hERG inactivated state. The results demonstrate that experimental data on specific drug interactions can be used as structural constraints to assess and refine hERG homology models.
Journal of the American Chemical Society, 1979
Journal of the American Chemical Society, 1979
Biochemistry
Molecular dynamics simulations of bee venom apamin, and an analogue having an Asn to Ala substitu... more Molecular dynamics simulations of bee venom apamin, and an analogue having an Asn to Ala substitution at residue 2 (apamin-N2A), were analyzed to explore the contribution of hydrogen bonds involving Asn2 to local (beta-turn residues N2, C3, K4, A5) and global stability. The wild-type peptide retained a stable conformation during 2.4 ns of simulation at 67 degrees C, with high beta-turn stability characterized by backbone-side chain hydrogen bonds involving beta-turn residues K4 and A5, with the N2 side chain amide carbonyl. The loss of stabilizing interactions involving the N2 side chain resulted in the loss of the beta-turn conformation in the apamin N2A simulations (27 or 67 degrees C). This loss of beta-turn stability propagates throughout the peptide structure, with destabilization of the C-terminal helix connected to the N-terminal region by two disulfide bonds. Backbone stability in a synthetic peptide analogue (apamin-N2A) was characterized by NMR and amide hydrogen exchange measurements. Consistent with the simulations, loss of hydrogen bonds involving the N2 side chain resulted in destabilization of both the N-terminal beta-turn and the C-terminal helix. Amide exchange protection factors in the C-terminal helix were reduced by 9-11-fold in apamin N2A as compared with apamin, corresponding to free energy (deltaDeltaG(uf)) of around 1.5 kcal M(-1) at 20 degrees C. This is equivalent to the contribution of hydrogen bond interactions involving the N2 side chain to the stability of the beta-turn. Together with additional measures of exchange protection factors, the three main contributions to backbone stability in apamin that account for virtually the full thermodynamic stability of the peptide have been quantitated.
Biochemistry
Molecular dynamics simulations of bee venom apamin, and an analogue having an Asn to Ala substitu... more Molecular dynamics simulations of bee venom apamin, and an analogue having an Asn to Ala substitution at residue 2 (apamin-N2A), were analyzed to explore the contribution of hydrogen bonds involving Asn2 to local (beta-turn residues N2, C3, K4, A5) and global stability. The wild-type peptide retained a stable conformation during 2.4 ns of simulation at 67 degrees C, with high beta-turn stability characterized by backbone-side chain hydrogen bonds involving beta-turn residues K4 and A5, with the N2 side chain amide carbonyl. The loss of stabilizing interactions involving the N2 side chain resulted in the loss of the beta-turn conformation in the apamin N2A simulations (27 or 67 degrees C). This loss of beta-turn stability propagates throughout the peptide structure, with destabilization of the C-terminal helix connected to the N-terminal region by two disulfide bonds. Backbone stability in a synthetic peptide analogue (apamin-N2A) was characterized by NMR and amide hydrogen exchange measurements. Consistent with the simulations, loss of hydrogen bonds involving the N2 side chain resulted in destabilization of both the N-terminal beta-turn and the C-terminal helix. Amide exchange protection factors in the C-terminal helix were reduced by 9-11-fold in apamin N2A as compared with apamin, corresponding to free energy (deltaDeltaG(uf)) of around 1.5 kcal M(-1) at 20 degrees C. This is equivalent to the contribution of hydrogen bond interactions involving the N2 side chain to the stability of the beta-turn. Together with additional measures of exchange protection factors, the three main contributions to backbone stability in apamin that account for virtually the full thermodynamic stability of the peptide have been quantitated.
Journal of the Chemical Society, Perkin Transactions 2, 1985
ABSTRACT
Journal of the Chemical Society, Perkin Transactions 2, 1985
ABSTRACT
Journal of the Chemical Society, Chemical Communications, 1977
ABSTRACT
Journal of the Chemical Society, Chemical Communications, 1977
ABSTRACT
Journal of the Chemical Society, Chemical Communications, 1983
ABSTRACT
Journal of the Chemical Society, Chemical Communications, 1983
ABSTRACT
Journal of the Chemical Society, Perkin Transactions 1, 1982
Page 1. 1982 603 Reductive Cleavage of Propellane-type Hydrazinium Dications as a Route to Medium... more Page 1. 1982 603 Reductive Cleavage of Propellane-type Hydrazinium Dications as a Route to Medium-sized Ring Bicyclic Diamines with Bridgehead Nitrogen Atoms By Roger W. Alder," Richard 8. Sessions, Andrew J. Bennet ...
Journal of the Chemical Society, Perkin Transactions 1, 1982
Page 1. 1982 603 Reductive Cleavage of Propellane-type Hydrazinium Dications as a Route to Medium... more Page 1. 1982 603 Reductive Cleavage of Propellane-type Hydrazinium Dications as a Route to Medium-sized Ring Bicyclic Diamines with Bridgehead Nitrogen Atoms By Roger W. Alder," Richard 8. Sessions, Andrew J. Bennet ...
Molecular Modelling, Synthesis, and Biological Activity of Methyl 3-Methyljasmonate and Related D... more Molecular Modelling, Synthesis, and Biological Activity of Methyl 3-Methyljasmonate and Related Derivatives.
Molecular Modelling, Synthesis, and Biological Activity of Methyl 3-Methyljasmonate and Related D... more Molecular Modelling, Synthesis, and Biological Activity of Methyl 3-Methyljasmonate and Related Derivatives.
Amino, Nitrosco and Nitro Compounds and Their Derivatives: Vol. 2 (1982), 1982
Page 1. CHAPTER 18 Special properties of di-and poly-amines ROGER W. ALDER School of Chemistry, U... more Page 1. CHAPTER 18 Special properties of di-and poly-amines ROGER W. ALDER School of Chemistry, University of Bristol, Bristol BS8 1 TS, England RICHARD B. SESSIONS lnstitut Le Be/, Universite Louis Pasteur, 1 Rue Blaise Pascal, 67008 Strasbourg, France ...
Amino, Nitrosco and Nitro Compounds and Their Derivatives: Vol. 2 (1982), 1982
Page 1. CHAPTER 18 Special properties of di-and poly-amines ROGER W. ALDER School of Chemistry, U... more Page 1. CHAPTER 18 Special properties of di-and poly-amines ROGER W. ALDER School of Chemistry, University of Bristol, Bristol BS8 1 TS, England RICHARD B. SESSIONS lnstitut Le Be/, Universite Louis Pasteur, 1 Rue Blaise Pascal, 67008 Strasbourg, France ...
Journal of the Chemical Society, Chemical Communications, 1992
A genetically engineered version of Bacillus stearothermophilus lactate dehydrogenase, incorporat... more A genetically engineered version of Bacillus stearothermophilus lactate dehydrogenase, incorporating structural motifs which serve to alter substrate specificity i n favour of a-keto acids with bulky aliphatic side chains, was used t o effect enantioselective reduction o f 4-methyl-2-oxopent-3-enoic acid.
Journal of the Chemical Society, Chemical Communications, 1992
A genetically engineered version of Bacillus stearothermophilus lactate dehydrogenase, incorporat... more A genetically engineered version of Bacillus stearothermophilus lactate dehydrogenase, incorporating structural motifs which serve to alter substrate specificity i n favour of a-keto acids with bulky aliphatic side chains, was used t o effect enantioselective reduction o f 4-methyl-2-oxopent-3-enoic acid.
Uploads
Papers by Richard Sessions