Protein mechanical unfolding: Importance of non-native interactions.

Mechanical unfolding of the fourth domain of Distyostelium discoideum filamin (DDFLN4) was studied by all-atom molecular dynamics simulations, using the GROMOS96 force field 43a1 and the simple point charge explicit water solvent. Our study reveals an important role of non-native interactions in the unfolding process. Namely, the existence of a peak centered at the end-to-end extension DeltaR approximately 22 nm in the force-extension curve is associated with breaking of non-native hydrogen bonds. Such a peak has been observed in experiments but not in Go models, where non-native interactions are neglected. We predict that an additional peak occurs at DeltaR approximately 2 nm using not only GROMOS96 force field 43a1 but also Amber 94 and OPLS force fields. This result would stimulate further experimental studies on elastic properties of DDFLN4.

[1]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[2]  Graham Richards,et al.  Intermolecular forces , 1978, Nature.

[3]  Angelika A Noegel,et al.  A mechanical unfolding intermediate in an actin-crosslinking protein , 2004, Nature Structural &Molecular Biology.

[4]  Chin-Kun Hu,et al.  Free energy landscape and folding mechanism of a β‐hairpin in explicit water: A replica exchange molecular dynamics study , 2005, Proteins.

[5]  Mai Suan Li,et al.  Dependence of protein mechanical unfolding pathways on pulling speeds. , 2009, The Journal of chemical physics.

[6]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[7]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[8]  Chin-Kun Hu,et al.  Refolding upon force quench and pathways of mechanical and thermal unfolding of ubiquitin. , 2006, Biophysical journal.

[9]  M. Rief,et al.  The folding pathway of a fast‐folding immunoglobulin domain revealed by single‐molecule mechanical experiments , 2005, EMBO reports.

[10]  Mai Suan Li,et al.  Secondary structure, mechanical stability, and location of transition state of proteins. , 2007, Biophysical journal.

[11]  Berk Hess,et al.  LINCS: A linear constraint solver for molecular simulations , 1997 .

[12]  J. Hartwig,et al.  Filamins as integrators of cell mechanics and signalling , 2001, Nature Reviews Molecular Cell Biology.

[13]  R. Dror,et al.  Long-timescale molecular dynamics simulations of protein structure and function. , 2009, Current opinion in structural biology.

[14]  R. M. Simmons,et al.  Elasticity and unfolding of single molecules of the giant muscle protein titin , 1997, Nature.

[15]  S. Radford,et al.  Mechanical resistance of proteins explained using simple molecular models. , 2006, Biophysical journal.

[16]  Berk Hess,et al.  GROMACS 3.0: a package for molecular simulation and trajectory analysis , 2001 .

[17]  J. Onuchic,et al.  Topological and energetic factors: what determines the structural details of the transition state ensemble and "en-route" intermediates for protein folding? An investigation for small globular proteins. , 2000, Journal of molecular biology.

[18]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[19]  D. van der Spoel,et al.  GROMACS: A message-passing parallel molecular dynamics implementation , 1995 .

[20]  E. Evans,et al.  Dynamic strength of molecular adhesion bonds. , 1997, Biophysical journal.

[21]  M. Li,et al.  New method for deciphering free energy landscape of three-state proteins. , 2008, The Journal of chemical physics.

[22]  Nancy R Forde,et al.  Mechanical processes in biochemistry. , 2004, Annual review of biochemistry.

[23]  Klaus Schulten,et al.  Mechanical unfolding intermediates in titin modules , 1999, Nature.

[24]  M. Rief,et al.  Reversible unfolding of individual titin immunoglobulin domains by AFM. , 1997, Science.

[25]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[26]  K. Schulten,et al.  Unfolding of titin immunoglobulin domains by steered molecular dynamics simulation. , 1998, Biophysical journal.

[27]  W. L. Jorgensen,et al.  Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids , 1996 .

[28]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .