Ernest Mehler, Ph.D.
LC-501 C -- 1300 York Ave.
Molecular Biophysics of Proteins and Nucleic Acids
Electrostatics and solvation effects play key roles in the structure and function of proteins, and one goal of our work is to develop computational methods to describe these effects. pH dependent properties, such as the protonation states of the titratable residues in proteins, are primarily dependent on the electrostatic component of the energy and we have developed a screened-Coulomb-potential based approach to calculate pKa values of the titratable residues in proteins. A particular strength of our approach is the incorporation of a quantitative description of the inhomogeneity of the protein interior. The program for calculating protonation states – MM_SCP, (Microenvironment Modulated-Screened Coulomb Potential).
A screened Coulomb potential based continuum solvent model has been developed and is being used for molecular dynamics and Monte Carlo simulations. These methods were applied earlier to calculate the structures of small peptides given only the sequence. Currently our activities are aimed at the calculation of the conformations of loops that connect known elements of secondary structure in proteins, and long time molecular dynamics simulations of small and medium sized proteins. The lab is continuing the development of these approaches to refine them with the aim of making them more reliable and computationally efficient.
The new computational modeling tools developed in the lab are being used to study structure and function of G protein coupled receptors (GPCRs). The loops connecting the trans-membrane helices are known to be involved in GPCR function, so that being able to accurately predict loop structure is essential for the study of GPCRs. Recently structures of the loops in the serotonin receptor were calculated, and with the help of rhodopsin the ability of the approach to yield loop structures in good agreement with experiment was demonstrated. Of special interest in future studies is how the binding of different ligands to GPCRs elicits differential responses in the loops. In particular, we are interested in the difference in response of the loops to hallucinogenic and non-hallucinogenic substances.
SOME RECENT PUBLICATIONS
- Periole, M.A. Ceruso, and E.L. Mehler. Acid-Base Equilibria in Rhodopsin: Dependence of the Protonation State of Glu 134 on Its Environment, Biochemistry, 43, 6858-64 (2004).
S.A. Hassan, E.L. Mehler, D. Zhang, and H Weinstein, Molecular Dynamics Simulations of Peptides and Proteins with an Implicit Solvent Model Based on Screened Coulomb Potentials. PROTEINS: Structure, Function and Genetics, 51, 109-125 (2003).
E.L. Mehler, X. Periole, S.A. Hassan, and H. Weinstein. Key issues in the Computational Simulation of GPCR Function: Representation of Loop Domains. J. Computer Aided Molecular Design, 16, 841-853 (2002).
E.L. Mehler, M. Fuxreiter and B. Garcia-Moreno E., The Role of Hydrophobic Microenvironments in Modulating pKa Shifts in Proteins. PROTEINS: Structure, Function and Genetics, 48, 283-292, (2002).
Sergio A. Hassan and Ernest L. Mehler, A Critical Analysis of the Screened Coulomb Potential-Implicit Solvent Model: Study of the Alanine Dipeptide and Discrimination of Misfolded Structures of Proteins. PROTEINS: Structure, Function and Genetics, 47, 45-61, (2002).
S.A. Hassan, E. L. Mehler and H. Weinstein, Structure Calculation of Protein Segments Connecting Domains with Defined Secondary Structure: A Simulated Annealing Monte Carlo Combined with Biased Scaled Collective Variables Technique. In: Hark K, Schlick T, editors. Lecture Notes in Computational Science and Engineering, Vol 24. Springer-Verlag AG, New York, 2002, 197-231.
S.A. Hassan and E.L. Mehler, A General Screened Coulomb Potential Based Implicit Solvent Model: Calculation of Secondary Structure of Small Peptides. Int. J. Quantum Chemistry, 83, 193-202, (2001).
- Tartaglia, E.L. Mehler, et al. Mutations in PTPN11, Encoding the Protein Tyrosine Phophatase SHP-2, cause Noonan Syndrome. Nature Genetics, 29, 465-468. (2001).
S.A. Hassan, F. Guarnieri, E.L. Mehler, A General Treatment of Solvent Effects Based on Screened Coulomb Potentials. J. Phys. Chem., 104, 6478-6489, (2000).
S.A. Hassan, F. Guarnieri, E.L. Mehler, Characterization Of Hydrogen Bonding In A Continuum Solvent Model. J. Phys. Chem., 104, 6490-6498, (2000).
E.L. Mehler and F. Guarnieri, A Self-Consistent, Microenvironment Modulated Approximation to Calculate pH Dependent Electrostatic Effects in Proteins. Biophys. J., 77. 3-22 (1999).