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Abstract Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process. (1) We simulate the ternary complex formation of SMARCA2 bromodomain and VHL E3 ligase by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics (MD). (2) We characterize the conformational heterogeneity of the ternary complex using Hamiltonian replica exchange simulations and small-angle X-ray scattering. (3) We assess the ubiquitination of the POI in the context of the full Cullin-RING Ligase, confirming experimental ubiquitinomics results. Differences in degradation efficiency can be explained by the proximity of lysine residues on the POI relative to ubiquitin. 

When cells take up material from their surroundings, they must first transport this cargo across their outer membrane, a flexible sheet of tightly organized fat molecules that act as a barrier to the environment. Cells can achieve this by letting their membrane surround the object, pulling it inwards until it is contained in a pouch that bulges into the cell. This bag is then corded up so it splits off from the outer membrane. The ‘cord’ is a protein called dynamin, which is thought to form a tight spiral around the bag’s neck, closing it over and pinching it away. The structure of dynamin is fairly well known, and yet several theories compete to explain how it may snap the bag off the outer membrane. Here, Pannuzzo et al. have created a computer simulation that faithfully replicates the geometry and the elasticity of the membrane and of dynamin, and used it to test different ways the protein could work. The first test featured simple constriction, where the dynamin spiral contracts around the membrane to pinch it; this only separated the bag from the membrane after implausibly tight constriction. The second test added elongation, with the spiral lengthening as well as reducing its diameter, but this further reduced the ability for the protein to snap off the membrane. The final test combined constriction and rotation, whereby dynamin ‘twirls’ as it presses on the neck of the bag: this succeeded in efficiently severing the membrane once the dynamin spiral disassembled. Indeed, the simulations suggested that dynamin might start to dismantle while it constricts, without compromising its role. In fact, getting rid of excess length as the protein contracts helps to dissolve any remnants of a membrane connection. Defects in dynamin are associated with conditions such as centronuclear myopathy and Charcot‐Marie‐Tooth peripheral neuropathy. Recent research also indicates that the protein is involved in a much wider range of neurological disorders that include Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The models created by Pannuzzo et al. are useful tools to understand how dynamin and similar proteins work and sometimes fail.