Propensity to form amyloid fibrils is encoded as excitations in the free energy landscape of monomeric proteins.
Protein aggregation, linked to many of diseases, is initiated when monomers access rogue conformations that are poised to form amyloid fibrils. We show, using simulations of src SH3 domain, that mechanical force enhances the population of the aggregation-prone (N(⁎)) states, which are rarely populated under force free native conditions but are encoded in the spectrum of native fluctuations. The folding phase diagrams of SH3 as a function of denaturant concentration ([C]), mechanical force (f), and temperature exhibit an apparent two-state behavior, without revealing the presence of the elusive N(⁎) states. Interestingly, the phase boundaries separating the folded and unfolded states at all [C] and f fall on a master curve, which can be quantitatively described using an analogy to superconductors in a magnetic field. The free energy profiles as a function of the molecular extension (R), which are accessible in pulling experiments, (R), reveal the presence of a native-like N(⁎) with a disordered solvent-exposed amino-terminal β-strand. The structure of the N(⁎) state is identical with that found in Fyn SH3 by NMR dispersion experiments. We show that the timescale for fibril formation can be estimated from the population of the N(⁎) state, determined by the free energy gap separating the native structure and the N(⁎) state, a finding that can be used to assess fibril forming tendencies of proteins. The structures of the N(⁎) state are used to show that oligomer formation and likely route to fibrils occur by a domain-swap mechanism in SH3 domain.
Biophysics Program, Institute for Physical Science and Technology, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
Pavel I
PI
Zhuravlev
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India.
Govardhan
G
Reddy
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215-2521, USA.
John E
JE
Straub
Biophysics Program, Institute for Physical Science and Technology, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. Electronic address: thirum@umd.edu.
D
D
Thirumalai
D000682:Amyloid / Q000737:chemistry; D003198:Computer Simulation; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D013057:Spectrum Analysis / Q000379:methods; D013816:Thermodynamics; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry
D000682:Amyloid; D019061:src-Family Kinases
phase diagram; protein aggregation; protein denaturation; self-organized polymer model; single-molecule force spectroscopy