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GTP-binding-protein ras, a signal-transducing protein involved in many cancers.  
:  GTP-bound, active form (GTP analog in sticks), 1LFO.pdb.  green:  GDP-bound, inactive form, 1LF5.pdb.

Mike Daily's Research webpage

CAPRI gallery, last updated 7/28/04

I am a second-year graduate student in the Program in Molecular Biophysics at Johns Hopkins University.

     Proper function of cells and organisms requires cells from different parts of the organism to act synchronously, and proteins within cells to communicate with each other through a process known as signal transduction.  These signaling pathways are involved in such processes as cell division regulation, optical and olfactory response, and hormone response.  Improper functioning of these pathways can lead to disease; for example, the malfunction of cell cycle control is the primary cause of many cancers.  Signal transduction is a higher-level form of enzyme regulation, not involving just the response of a single protein to environmental conditions, but often a whole network of proteins.  My research focuses on the use of biomolecular modeling techniques to predict the molecular mechanisms of signal transduction from known protein structures.  That is, given a perturbation in one portion of a protein structure, how do other portions of that protein’s structure respond? Two major models for this allostery in protein structures exist, mechanical perturbation and effector-induced shift in a preexisting conformational ensemble.  Using the Rosetta biomolecular modeling package, which predicts protein structures and protein-protein complexes to within 5A RMSD in 50-70 percent of targets, I intend to simulate how binding of allosteric effectors to proteins causes them to change conformations.  I intend to compare results from simulations based on the mechanical perturbation model to results from simulations based on the conformational ensemble model to shed light on which model is more biologically relevant.  My model systems will include such well-studied signal-transducing proteins like GTP-binding proteins (G-proteins) and MAP kinase, and possibly also well-studied allosteric enzymes like phosphofructokinase and hemoglobin.
    Shown above is the α subunit of the GTP-binding protein ras, an important intermediate in multiple signal-transduction pathways in inactive (GDP-bound) and active (GTP-bound) forms.  For example, ras is dysfunctional (unconditionally active) in 40-60 percent of cancer cases.  In its inactive (GDP-bound) state, ras exists as a heterotrimer, with the α subunit bound to Gβγ.  Three main regions of conformation change, called switch I, II, and III, respectively, can be observed.  It is the goal of this project to develop a simulation strategy based on Rosetta that will simulate the conformational change that occurs when ras exchanges GDP for GTP.

"User-friendly" project description
Old projects

The new Gray lab CAPRI paper is out!

CAPRI rounds 3-5 reveal promising successes and future challenges for RosettaDock.  M.D. Daily, D. Masica, A. Sivasubramanian, S. Somarouthu, and J.J. Gray (2005).  Proteins 60(2), 181-186.  web  PDF.

2004 Institute for Biophysical Research Retreat.  M. Daily, A. Sivasubramanian, D. Masica, and J. Gray.  "New Challenges in Protein Assembly and Function."  September 2004, Baltimore, MD. (poster).  PDF.

Biophysical Society 48th Annual Meeting
: J. Gray & D. Baker, "Protein-Protein Docking Predictions with RosettaDock." February 2004, Baltimore, MD. PDF

Modeling of Protein Interactions in Genomes: M. Daily, M. Ostermeier & J. Gray, "Modeling the Structural and Energetic Basis for Functional Coupling in Two Engineered Maltose Binding Protein/TEM-1 B-Lactamase Molecular Switches." June 2003, Stony Brook, NY. (poster) PDF

Prior to Hopkins:
Huyghues-Despointes, B.M., Thurlkill R.L., Daily, M.D., Schell, D., Briggs, J.M., Antiosewicz, J.M., Pace, C.N., and Scholtz., J.M.  (2003). pK Values of Histidine Residues in Ribonuclease Sa:  Effect of Salt and Net Charge.  JMB 325, 1093-1105.
Daily, M.D.  Local and Long-Range Electrostatic Interactions in Denatured RNase Sa:  Comparing the Denatured Protein with Model Peptides.  (Spring 2002).  Senior Thesis.  Texas A&M University.  J.M. Scholtz, advisor.

Tutorial links

Last updated 5/4/04