This lattice protein model defines fitness as the equilibrium probability of a fixed active-site motif and uses multicanonical sequence sampling to show how thermal fluctuations turn a local functional requirement into a global structural constraint.
Abstract
Foldable proteins exhibit funnel-like energy landscapes, but their evolution under selection for function remains unclear. We study this in a lattice protein model, defining fitness as the equilibrium probability of a fixed active-site motif and using multicanonical sequence sampling. At intermediate temperature, rare high-fitness sequences show funnel-like energy and double-well free-energy landscapes. At very low temperature, abundant high-fitness sequences retain glass-like landscapes. Thus, thermal fluctuations turn a local functional requirement into a global structural constraint.
This work reviews the computational and experimental approaches that disentangle folding and function at scale, revealing a dark energy component and providing new insights into how biological information flows from sequence to structure to function and back to sequence.
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