![]() ![]() This is the first such demonstration of the possibility that a “kinetic” effect may partly underlie the destabilized thermodynamics of binding of F19A and is a feature that appears to be conserved in evolution. The lack of the bulky sidechain of F in the F19A mutant results in the absence of the initial “grasp” complex, and hence the mutant peptide diffuses randomly on the surface of MDM2 without binding. This is similar to a crack forming in an otherwise occluded hydrophobic cavity in MDM2, and the peptide, docked through F19, modulates the propagation of this crack, which subsequently results in the stepwise docking of the rest of the peptide through insertions of W23 and L26. This initial step anchors the peptide onto the surface of MDM2, and with the consequent reduction in the search space of the peptide, the peptide docks into the partially occluded surface of MDM2. It starts with the capture of F19 of wild type p53 by certain residues in the MDM2 binding pocket. These simulations show that binding is characterized by a complex multistep process. Does this mutation also modulate the initial recognition between p53 and MDM2? We look at atomistic computer simulations of the process of the initial encounter between wild type p53 peptide and its F19A mutant with the N-terminal domain of MDM2. MacGregor said Wagner emailed him, “asking if we had flown over this area where the crack was spotted.”Īs fate would have it, Operation IceBridge had one flight left over Petermann Glacier for this year’s mission, and it was scheduled for the next day.Why doesn’t the F19A mutant of p53 bind to MDM2? Binding thermodynamics have suggested that the loss of packing interactions upon mutating Phe into Ala sidechain results in destabilizing the binding free energy between p53 and MDM2. ![]() MacGregor was in Greenland leading a unique research campaign called Operation IceBridge, which makes low-level flights over Greenland and Antarctica’s ice sheets to create 3-D views of the ice with the intent of understanding its rapid changes. Wagner pointed them out to a member of his team, Joe MacGregor. His tweets caught the attention of NASA’s program scientist for the cryosphere, Tom Wagner, who directs NASA’s polar research. Is this recent internal crack in #Petermann glacier the prelude of a new island? 1/5 /V8qKF1MwmC- Stef Lhermitte April 12, 2017 … I had a hypothesis but was not sure,” Lhermitte said. “Several of my initial tweets have question marks at the end. Lhermitte took his findings directly to Twitter, tweeting several images of the crack and searching for help determining its significance. ![]()
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