STATISTICAL-MECHANICS OF KINETIC PROOFREADING IN PROTEIN-FOLDING IN-VIVO

The statistical energy landscape picture of protein folding has led to the understanding that the energy landscape must have guiding forces leading to a protein folding funnel in order to avoid the Levinthal pa radox in vitro. Since folding in vivo often requires the action of cha perone molecules and ATP hydrolysis, we must ask whether folding in a system maintained away from equilibrium can avoid the Levinthal parado x in other ways. We describe a model of the action of chaperone molecu les in protein folding in vivo on the basis of a repetitive cycle of b inding and unbinding, allowing the possibility of kinetic proofreading . We also study models in which chaperone binding is locally biased, d epending on the similarity of the conformation to the native one. We s how that while kinetic proofreading can modestly facilitate folding, i t is insufficient by itself to overcome the Levinthal paradox. On the other hand, such kinetic proofreading with biasing can provide the non equilibrium analog of a folding funnel and greatly enhance folding yie lds and speed up folding.