• Hewafonsekage Y.Y. Fonseka, A. Javidi, L.F.L. Oliveira, C. Micheletti, and G. Stan
    Unfolding and Translocation of Knotted Proteins by Clp Biological Nanomachines: Synergistic Contribution of Primary Sequence and Topology Revealed by Molecular Dynamics Simulations
    J. Phys. Chem. B, 2021, 125 , 7335-7350
    Link to online article Cover article

  • Abstract
    We use Langevin dynamics simulations to model, at 7 an atomistic resolution, how various natively knotted proteins are 8 unfolded in repeated allosteric translocating cycles of the ClpY 9 ATPase. We consider proteins representative of different topologies, from the simplest knot (trefoil 3.1), to the three-twist 5.2 knot, to the most complex stevedore, 6.1, knot. We harness the atomistic detail of the simulations to address aspects that have so far remained largely unexplored, such as sequence-dependent effects on the ruggedness of the landscape traversed during knot sliding. Our simulations reveal the combined effect on translocation of the knotted protein structure, i.e., backbone topology and geometry, and primary sequence, i.e., side chain size and interactions, and show that the latter can dominate translocation hindrance. In addition, we observe that due to the interplay between the knotted topology and intramolecular contacts the transmission of tension along the peptide chain occurs veryd ifferently from that of homopolymers. Finally ,by considering native and non-native interactions, we examine how the disruption or formation of such contacts can affect the translocation processivity and concomitantly create multiple unfolding pathways with very different activation barriers.