Interaction Networks in Protein Folding via Atomic-Resolution Experiments and Long-Time-Scale Molecular Dynamics Simulations.
The integration of atomic-resolution experimental and computational methods offers the potential for elucidating key aspects of protein folding that are not revealed by either approach alone. Here, we combine equilibrium NMR measurements of thermal unfolding and long molecular dynamics simulations to investigate the folding of gpW, a protein with two-state-like, fast folding dynamics and cooperative equilibrium unfolding behavior. Experiments and simulations expose a remarkably complex pattern of structural changes that occur at the atomic level and from which the detailed network of residue-residue couplings associated with cooperative folding emerges. Such thermodynamic residue-residue couplings appear to be linked to the order of mechanistically significant events that take place during the folding process. Our results on gpW indicate that the methods employed in this study are likely to prove broadly applicable to the fine analysis of folding mechanisms in fast folding proteins.
†National Biotechnology Center, CSIC, Madrid 28049, Spain.
Lorenzo
L
Sborgi
†National Biotechnology Center, CSIC, Madrid 28049, Spain.
Abhinav
A
Verma
‡D. E. Shaw Research, New York, New York 10036, United States.
Stefano
S
Piana
‡D. E. Shaw Research, New York, New York 10036, United States.
Kresten
K
Lindorff-Larsen
†National Biotechnology Center, CSIC, Madrid 28049, Spain.
Michele
M
Cerminara
†National Biotechnology Center, CSIC, Madrid 28049, Spain.
Clara M
CM
Santiveri
‡D. E. Shaw Research, New York, New York 10036, United States.|§Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, United States.
David E
DE
Shaw
†National Biotechnology Center, CSIC, Madrid 28049, Spain.
Eva
E
de Alba
†National Biotechnology Center, CSIC, Madrid 28049, Spain.|∥School of Engineering, University of California, Merced, California 95343, United States.
Victor
V
Muñoz
D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors
D011506:Proteins