Folding/unfolding of mechanical proteins, binding/unbinding of non-covalently attached biomolecules, and selectivity of biological transmembrane ion channels are at the heart of many important processes like muscle stretching, immune response, electrical signaling, and are the target of experimental and theoretical investigations. Dr. Schulten proposes to use Steered Molecular Dynamics (SMD) simulations, a tool that allows one to investigate processes which cannot be easily detected in experiments, to: 1) understand how the architecture of sandwich domains in the immunoglobulin (Ig) and fibronectin type III (FnIII) domains of titin has served nature to design proteins which can withstand high forces and act as stress sensors, and resolve at the atomic level the mechanical stretching and unfolding of protein domains by forced unfolding of the Ig and FnIII domains; 2) quantify changes in the protein flexibility connected with antibody maturation and investigate hapten interactions with residues of the binding pocket by inducing the unbinding of the hapten; 3) determine the potential of mean force and explain the basis for the fidelity with which the K+ channel distinguishes between K+ and Na+ ions, and for the selectivity encoded in the signature sequence of the K+ channel by simulating the passing of K+ ions through the channel. These studies will provide results that can be directly compared to experimental data, as well as complement observations through atomic-level details of these processes explaining the data.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060946-03
Application #
6520182
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Wehrle, Janna P
Project Start
2000-04-01
Project End
2003-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$168,537
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Type
Organized Research Units
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Craig, David; Gao, Mu; Schulten, Klaus et al. (2004) Structural insights into how the MIDAS ion stabilizes integrin binding to an RGD peptide under force. Structure 12:2049-58
Park, Sanghyun; Schulten, Klaus (2004) Calculating potentials of mean force from steered molecular dynamics simulations. J Chem Phys 120:5946-61
Craig, David; Gao, Mu; Schulten, Klaus et al. (2004) Tuning the mechanical stability of fibronectin type III modules through sequence variations. Structure 12:21-30
Roux, Benoit; Schulten, Klaus (2004) Computational studies of membrane channels. Structure 12:1343-51
Cohen, Jordi; Schulten, Klaus (2004) Mechanism of anionic conduction across ClC. Biophys J 86:836-45
Gao, Mu; Craig, David; Lequin, Olivier et al. (2003) Structure and functional significance of mechanically unfolded fibronectin type III1 intermediates. Proc Natl Acad Sci U S A 100:14784-9
Grayson, Paul; Tajkhorshid, Emad; Schulten, Klaus (2003) Mechanisms of selectivity in channels and enzymes studied with interactive molecular dynamics. Biophys J 85:36-48
Bayas, M V; Schulten, K; Leckband, D (2003) Forced detachment of the CD2-CD58 complex. Biophys J 84:2223-33
Gao, Mu; Wilmanns, Matthias; Schulten, Klaus (2002) Steered molecular dynamics studies of titin I1 domain unfolding. Biophys J 83:3435-45
Gao, Mu; Craig, David; Vogel, Viola et al. (2002) Identifying unfolding intermediates of FN-III(10) by steered molecular dynamics. J Mol Biol 323:939-50

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