What sets the folding speed limit and internal friction? · revision history

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Revision 1: What sets the folding speed limit and internal friction
Revision 2: What sets the folding speed limit and internal friction?
Plain
The fastest proteins fold in about a microsecond, and theory and experiment suggest a floor of roughly N/100 microseconds for a chain of N amino acids. The question is which physical process sets this floor: the chain moving through water, or friction inside the chain itself.
Precise
For ultrafast folders (villin headpiece, WW domains; folding times $\sim 1 \text{ to } 10\ \mathrm{microseconds}$), determine the prefactor $k_0$ in the Kramers rate $k = k_0 \exp(-dG/k_B T)$, with the empirical estimate $\tau_{\min} \sim N/100\ \mathrm{microseconds}$ for $N$ residues (Kubelka, Hofrichter and Eaton, 2004), and separate solvent from internal friction through the viscosity dependence $\tau = a\eta + b$ at fixed stability ($\eta = \text{solvent viscosity}$). An answer gives $k_0$ and the internal-friction term $b$ with their molecular origin (backbone dihedral barriers, side-chain contacts) and reproduces measured $\eta$-dependences.
Settled by
Viscosity-dependent single-molecule transition-path and folding-time measurements on ultrafast folders matched by all-atom or coarse-grained simulations that identify the friction source.
Kind
well-posed
Answer type
mechanism
References
(empty)
Literature status
partially-resolved
Status note
Single-molecule measurements since 2012 bound transition-path times at microseconds; the molecular origin of internal friction is still disputed as of 2026, to this survey's knowledge.
Posed since
2004

Decisions