Structural basis of PROTAC cooperative recognition for selective protein degradation

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation

Dislocation multi-junctions and strain hardening

At the microscopic scale, the strength of a crystal derives from the motion, multiplication and interaction of distinctive line defects--dislocations. First theorized in 1934 to explain low magnitudes of crystal strength observed experimentally, the existence of dislocations was confirmed only two decades later. Much of the research in dislocation physics has since focused on dislocation interactions and their role in strain hardening: a common phenomenon in which continued deformation increases a crystal's strength. The existing theory relates strain hardening to pair-wise dislocation reactions in which two intersecting dislocations form junctions tying dislocations together. Here we report that interactions among three dislocations result in the formation of unusual elements of dislocation network topology, termed hereafter multi-junctions. The existence of multi-junctions is first predicted by Dislocation Dynamics (DD) and atomistic simulations and then confirmed by the transmission electron microscopy (TEM) experiments in single crystal molybdenum. In large-scale Dislocation Dynamics simulations, multi-junctions present very strong, nearly indestructible, obstacles to dislocation motion and furnish new sources for dislocation multiplication thereby playing an essential role in the evolution of dislocation microstructure and strength of deforming crystals. Simulation analyses conclude that multi-junctions are responsible for the strong orientation dependence of strain hardening in BCC crystals

Probing the limits of metal plasticity with molecular dynamics simulations

Ordinarily, the strength and plasticity properties of a metal are defined by dislocations—line defects in the crystal lattice whose motion results in material slippage along lattice planes1. Dislocation dynamics models are usually used as mesoscale proxies for true atomistic dynamics, which are computationally expensive to perform routinely2. However, atomistic simulations accurately capture every possible mechanism of material response, resolving every “jiggle and wiggle”3 of atomic motion, whereas dislocation dynamics models do not. Here we present fully dynamic atomistic simulations of bulk single-crystal plasticity in the body-centred-cubic metal tantalum. Our goal is to quantify the conditions under which the limits of dislocation-mediated plasticity are reached and to understand what happens to the metal beyond any such limit. In our simulations, the metal is compressed at ultrahigh strain rates along its [001] crystal axis under conditions of constant pressure, temperature and strain rate. To address the complexity of crystal plasticity processes on the length scales (85–340 nm) and timescales (1 ns–1μs) that we examine, we use recently developed methods of in situ computational microscopy4, 5 to recast the enormous amount of transient trajectory data generated in our simulations into a form that can be analysed by a human. Our simulations predict that, on reaching certain limiting conditions of strain, dislocations alone can no longer relieve mechanical loads; instead, another mechanism, known as deformation twinning (the sudden re-orientation of the crystal lattice6), takes over as the dominant mode of dynamic response. Below this limit, the metal assumes a strain-path-independent steady state of plastic flow in which the flow stress and the dislocation density remain constant as long as the conditions of straining thereafter remain unchanged. In this distinct state, tantalum flows like a viscous fluid while retaining its crystal lattice and remaining a strong and stiff metal

Discrete Dislocation Dynamics Simulations of Irradiation Hardening in Nuclear Materials

Neutron irradiation can severely impact the mechanical behavior of nuclear structural materials. Irradiation introduces a high density of nanometric defects that block dislocation motion and result in hardening and a loss of ductility often associated with the onset of localized plastic flow in a highly heterogeneous manner. In our hierarchy of numerical methods used to understand and quantify mechanical property degradation under irradiation, discrete dislocation dynamics (DD) provides a window into the time and length scales where critical interactions between dislocations and defects occur. In the present chapter, we discuss the current state of the art of DD simulations applied to irradiation scenarios, introducing the theoretical models devised to deal with dislocation-defect interactions, crystal structure particularities, and the most salient aspects of several highlighted applications. We also discuss current limitations and what new understanding has been gained vis-a-vis serviceable nuclear materials using these techniques

Continuum Dislocation Dynamics: Classical Theory and Contemporary Models

The continuum theory of dislocation fields is discussed in this chapter with an emphasis on the formulations relevant to infinitesimal deformation of single crystals. Both the classical and contemporary developments are concisely outlined. The classical theory of dislocation fields is introduced first for static and dynamic dislocation configurations, followed by a brief discussion of the shortcomings of the classical theory in predicting plasticity of crystals. In this regard, the lack of connection between the evolution of the dislocation field and internal stress state of the crystal is particularly highlighted. The more recent phenomenological and statistically-based formalisms of continuum dislocation dynamics are then introduced. As discussed in the pertinent sections, these formalisms properly connect the evolution of the dislocation fields with the internal stress state in and thus offer frameworks for predicting the plastic behavior of crystals