Ernest L. Mehler 
Cathepsin L

Research Associate Professor
Ph.D., Iowa State University
Postdoctoral training: University of Washington
(212) 241-5852
E-mail address: mehler@inka.mssm.edu

Molecular Biophysics of Proteins and Nucleic Acids: Structure, Function and Electrostatic Properties

The research of this laboratory is directed toward two different goals: A) The study of structure-function relations in Ca-binding proteins such as calmodulin and troponinC. Structural and functional characterization of membrane bound proteins immersed in the membrane and the role of the membrane in controlling and modulating the actions of these proteins. The principal method used in these studies is Molecular Dynamics Simulation. B) The second goal of our research efforts is to develop accurate and fast methods for describing electrostatic and solvation effects in biological macromolecules. These developments will be used to study properties that are dependent on electrostatic interactions and to describe bulk solvent effects implicitly for use with Monte Carlo and Molecular Dynamics simulations.
 
 

  • Signal transduction by Ca2+

    • Structural and dynamic characteristics of calmodulin [1] in solution. The Ca2+ signal is decoded by binding to the EF-hand motif leading to a structural change that activates the protein: Structural and Dynamic Relationships between Apo - and Ca2+-loaded Calmodulin
     
     
     
     
     
  • Membranes and membrane bound proteins


    • The molecular dynamics (MD)  of fully hydrated patches of dimyristoyl phosphatidylcholine (DMPC) bilayers  were  simulated [2] for 1.5 nanoseconds. The effects of embedding a helical protein domain in the patch was studied from a 2.5 nanosecond MD simulation. The figure shows the membrane-helical protein complex embedded in water at the end of the 2.5 nanosecond simulation. The lipid head group is shown in the CPK representation with phosphates (purple), nitrogen atoms (blue) and glycerol oxygens (red). The strong kink in the a helix developed during the course of the simulation.
     
     
     
     
  • Electrostatics and Solvation: Structure prediction from sequence


    • A. The calculation of pH dependent electrostatic effects [click here for information to get pK program], such as the protonation state of titratable groups in proteins, uses screened Coulomb potentials [3,4] and a quantitative representation of local environments to achieve highly reliable results. The figure shows Glu 35, in lysozyme,  and its surrounding amino acid residues. The color coding indicates the degree of hydrophobicity of each residue: blue for hydrophilic residues and red-orange for hydrophobic residues. The microenvironment of Glu 35 is very hydrophobic leading to the upward shift in its pKa that favors the protonated state relative to water.
     
     
     


    B. A  screened Coulomb potential based implicit solvent model [5,6]  for use with Monte Carlo and Molecular Dynamics simulations is being used to calculate the structures of small peptides given only the sequence. The method has been applied to several peptides including the 15 residue peptide (shown in the figure) that is known to form an a-helix. The figure shows representative structures found from a conformational search that starts from a completely extended conformation. A structure with one helical turn is shown in (A), two helical turns in (B) and three turns in (C). The calculated extent of helicity exhibited by each amino acid residue in the peptide is in good agreement with experiment [7].
     
     
     
     

    RECENT PUBLICATIONS
     
     

    [1] Wriggers, W., Mehler, E., Pitici, F., Weinstein, H. and Schulten, K. (1998). Structure and Dynamics of Calmodulin in Solution.Biophys. J. 74: 1622-1639.

    [2] Duong, T. H., Mehler, E. L. and Weinstein, H. (1999). Molecular Dynamics Simulation of Membranes and a Transmembrane Helix. J. Comp. Phys  151: 358-387.

    [3] Mehler, E. L. and Guarnieri, F. (1999). A Self-Consistent, Microenvironment Modulated Screened Coulomb Potential Approximation to Calculate pH Dependent Electrostatic Effects in Proteins. Biophysics J. 77: 3-22.

    [4] Luo, N., Mehler, E. and Osman, R.. (1999). Specificity and Catalysis of Uracil DNA Glycosylase. Molecular Dynamics Study of Reactant and Product Complexes with DNA. Biochemistry38: 9209-9220.

    [5] Hassan, S.A., Guarnieri, F., Mehler, E.L. (2000) A General Treatment of Solvent Effects Based on Screened Coulomb Potentials. J. Phys. Chem., 104: 6478-6489.

    [6] Hassan, S.A., Guarnieri, F., Mehler, E.L. (2000) Characterization of Hydrogen Bonding in a Continuum Solvent Model. J. Phys. Chem., 104: 6490-6498.

    [7] Hassan,S.A. and Mehler, E.L. (in press) A General Screened Coulomb Potential Based Implicit Solvent Model: Calculation of Secondary Structure of Small Peptides. Int. J. Quantum Chemistry.

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    Last update: 3/8/2001 - elm