title: pH Dependence of a 310-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study.
abstract: Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a 310-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains, and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G* and B3LYP/6-31+G*:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a 310-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules.
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500046 India, Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India, and Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: Dandamudi
authors.initials: D
authors.lastname: Usharani
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500046 India, Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India, and Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: Palakuri
authors.initials: P
authors.lastname: Srivani
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500046 India, Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India, and Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: G Narahari
authors.initials: GN
authors.lastname: Sastry
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500046 India, Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India, and Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: Eluvathingal D
authors.initials: ED
authors.lastname: Jemmis