TY - JOUR T1 - Knotting a Protein in Explicit Solvent JF - The Journal of Physical Chemistry Letters Y1 - 2013 A1 - Jeffrey K. Noel A1 - José N. Onuchic A1 - Joanna I. Sulkowska AB - Recently, experiments have confirmed that trefoil knotted proteins can fold spontaneously, consistent with predictions from simulations of simplified protein models. These simulations suggest folding the knot involves threading the protein terminal across a twisted loop via a slipknot configuration. Here, we report unbiased all-atom explicit-solvent simulations of the knotting dynamics of a protein. In simulations totaling 40 μs, we find that 5 out of 15 simulations reach the knotted native state when initiated from unknotted, slipknotted intermediates. The completed threading events had durations of 0.1–2 μs. Comparison of explicit-solvent to structure-based simulations shows that similar native contacts are responsible for threading the slipknot through the loop; however, competition between native and non-native salt bridges during threading results in increased energetic roughness. Overall, these simulations support a slipknotting mechanism for proteins with complex topology, and help verify that simplified models are useful tools for studying knotted proteins. VL - 4 UR - http://pubs.acs.org/doi/abs/10.1021/jz401842f ER -