Molecular simulations of chaperonins

Chaperonins are a class of cage-like molecular machines that assist the folding of polypeptides by binding and releasing non-native substrates into their inner cavity, where sequestered from the medium the substrate can fold to its native state. The main goal of this work is to understand the structure-function relationship of chaperonin. Here we study two major aspects of this relationship: (1) thermodynamics of protein folding inside the chaperonin cavity and (2) conformational changes of the E. coli chaperonin GroEL in its reaction cycle. We have studied the thermodynamics of protein folding, confined in the chaperonin cavity using the simple HP model of protein undergoing the coil-to-globule transition. Using the Wang-Landau method we have quantified the increase in thermal stability of a native state in a spherical confining geometry; measured as an increase in melting temperature with decreasing radius of confining sphere. We are the first to show that the t → r transition in GroEL subunit occurs spontaneously using unbiased molecular dynamics simulation. The transition pathway is shown to lie along low frequency quasi-harmonic modes of vibration. We are also the first to observe the spontaneous insertion of Ala480 into the empty nucleotide binding pocket, required for negative interring cooperativity.