Levinthal's paradox.
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TL;DR
Mathematical analysis of a simple model shows that a small and physically reasonable energy bias against locally unfavorable configurations, of the order of a few kT, can reduce Levinthal's time to a biologically significant size.
Abstract
Levinthal's paradox is that finding the native folded state of a protein by a random search among all possible configurations can take an enormously long time. Yet proteins can fold in seconds or less. Mathematical analysis of a simple model shows that a small and physically reasonable energy bias against locally unfavorable configurations, of the order of a few kT, can reduce Levinthal's time to a biologically significant size.