Dynamic Length Scale and Weakest Link Behavior in Crystal Plasticity

Plastic deformation of heterogeneous solid structures is often characterized by random intermittent local plastic events. On the mesoscale this feature can be represented by a spatially fluctuating local yield threshold. Here we study the validity of such an approach and the ideal choice for the size of the representative volume element for crystal plasticity in terms of a discrete dislocation model. We find that the number of links representing possible sources of plastic activity exhibits anomalous (super-extensive) scaling which tends to extensive scaling (often assumed in weakest-link models) if quenched short-range interactions are introduced. The reason is that the interplay between long-range dislocation interactions and short-range quenched disorder destroys scale-free dynamical correlations leading to event localization with a characteristic length-scale. Several methods are presented to determine the dynamic length-scale that can be generalized to other types of heterogeneous materials

Mechanism-Based Redesign of GAP to Activate Oncogenic Ras

Ras GTPases play a crucial role in cell signaling pathways. Mutations of the Ras gene occur in about one third of cancerous cell lines and are often associated with detrimental clinical prognosis. Hot spot residues Gly12, Gly13, and Gln61 cover 97% of oncogenic mutations, which impair the enzymatic activity in Ras. Using QM/MM free energy calculations, we present a two-step mechanism for the GTP hydrolysis catalyzed by the wild-type Ras.GAP complex. We found that the deprotonation of the catalytic water takes place via the Gln61 as a transient Brønsted base. We also determined the reaction profiles for key oncogenic Ras mutants G12D and G12C using QM/MM minimizations, matching the experimentally observed loss of catalytic activity, thereby validating our reaction mechanism. Using the optimized reaction paths, we devised a fast and accurate procedure to design GAP mutants that activate G12D Ras. We replaced GAP residues near the active site and determined the activation barrier for 190 single mutants. We furthermore built a machine learning for ultrafast screening, by fast prediction of the barrier heights, tested both on the single and double mutations. This work demonstrates that fast and accurate screening can be accomplished via QM/MM reaction path optimizations to design protein sequences with increased catalytic activity. Several GAP mutations are predicted to re-enable catalysis in oncogenic G12D, offering a promising avenue to overcome aberrant Ras-driven signal transduction by activating enzymatic activity instead of inhibition. The outlined computational screening protocol is readily applicable for designing ligands and cofactors analogously

Toward Understanding CB[7]-Based Supramolecular Diels-Alder Catalysis

Cucurbiturils (CBs) are robust and versatile macrocyclic compounds, often used as molecular hosts in complex supramolecular systems. In previous work, remarkable catalytic activity has been observed for asymmetric cycloadditions under very mild conditions. Herein, we investigate the nature of supramolecular catalysis using DFT calculations and QM/MM techniques. We discuss induced conformational changes, electrostatic shielding effects from the highly polar aqueous environment and cooperativity in hydrogen bonding of the substrates in explicit water using QM/MM simulation techniques. Our results show little specificity for the chosen molecules, suggesting an excellent opportunity to expand the scope for catalytic use of these supramolecular macrocyclic containers

Resolving sub-angstrom ambient motion through reconstruction from vibrational spectra.

Metal/organic-molecule interactions underpin many key chemistries but occur on sub-nm scales where nanoscale visualisation techniques tend to average over heterogeneous distributions. Single molecule imaging techniques at the atomic scale have found it challenging to track chemical behaviour under ambient conditions. Surface-enhanced Raman spectroscopy can optically monitor the vibrations of single molecules but understanding is limited by the complexity of spectra and mismatch between theory and experiment. We demonstrate that spectra from an optically generated metallic adatom near a molecule of interest can be inverted into dynamic sub-Å metal-molecule interactions using a comprehensive model, revealing anomalous diffusion of a single atom. Transient metal-organic coordination bonds chemically perturb molecular functional groups > 10 bonds away. With continuous improvements in computational methods for modelling large and complex molecular systems, this technique will become increasingly applicable to accurately tracking more complex chemistries.We acknowledge financial support from EPSRC grant EP/G060649/1, EP/L027151/1, EP/G037221/1, EP/R013012/1, EPSRC NanoDTC, and EU grant THOR 829067 and ERC starting grant BioNet 757850. B.d.N. acknowledges support from the Leverhulme Trust and Isaac Newton Trust. We acknowledge use of the Rosalind computing facility at King’s College London. We are grateful to the UK Materials and Molecular Modelling Hub for computational resources, which is partially funded by EPSRC 397 (EP/P020194/1)

Optical probes of molecules as nano-mechanical switches

Abstract: Molecular electronics promises a new generation of ultralow-energy information technologies, based around functional molecular junctions. Here, we report optical probing that exploits a gold nanoparticle in a plasmonic nanocavity geometry used as one terminal of a well-defined molecular junction, deposited as a self-assembled molecular monolayer on flat gold. A conductive transparent cantilever electrically contacts individual nanoparticles while maintaining optical access to the molecular junction. Optical readout of molecular structure in the junction reveals ultralow-energy switching of ∼50 zJ, from a nano-electromechanical torsion spring at the single molecule level. Real-time Raman measurements show these electronic device characteristics are directly affected by this molecular torsion, which can be explained using a simple circuit model based on junction capacitances, confirmed by density functional theory calculations. This nanomechanical degree of freedom is normally invisible and ignored in electrical transport measurements but is vital to the design and exploitation of molecules as quantum-coherent electronic nanodevices

Distinct cytokine patterns may regulate the severity of neonatal asphyxia

Abstract Background Neuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome. Methods We analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n = 17) and a severe (n = 11) group based on neuroradiological and amplitude-integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high-performance liquid chromatography. Results The prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF-α in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-α were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-β levels were increased from 24 h onwards in the moderate group. Conclusions IL-1β and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-α seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia

Local Yield Stresses in 2D Dislocation Systems

Studies on amorphous materials show that the concept of local yield stress can be used to link structural properties to plastic activity. An analogous threshold can be defined in crystalline materials. In the present work this local quantity is studied within the framework of 2D DDD simulations. The results show that local yield stresses obey the Weibull distribution and the local yield stresses of regions and the ones of their softest subsystems show remarkably high correlation

Chemical and Enzymatic Catalysis from a Computational Perspective

Herein I present the computational study of four (bio)chemical systems. I employed classical atomistic simulations as well as DFT calculations and hybrid QM/MM methods to gain structural insight and understanding of the catalytic function therein. This thesis covers two enzymes: the RNA helicase of SARS-CoV-2 and the human Ras GTPase. The presented helicase model demonstrates the importance of detailed modelling of holoproteins. Through extended classical simulations, we access the statistics and dynamics of substrate and allosteric pockets, ideal for building a specific drug development strategy. In contrast with the helicase, Ras GTPases have long been in the spotlight of research, yet they present a formidable challenge in cancer treatment. We elaborate the mechanistic possibilities and conclude that a base assisted pathway is preferred in the enzymatic environment. The model relies on the QM description of the crucial proton transfer steps, invisible to most experiments. The proposed mechanism is consistent with the reactivity of intrinsic and mutant Ras. Furthermore, a novel screening algorithm is developed to restore the lost activity in Ras mutants by mutations on its activating protein GAP. Although chemical catalysis is seldom as effective as enzymes evolved in million years, they constitute an important basis for chemical industries. Two sustainable and efficient catalytic systems are presented in this thesis. We provide an explanation to the catalytic effect of the supramolecular CB[7] on model Diels-Alder reactions, by analysing a number of factors the macrocycle influences. Most importantly, the substrate-solvent interaction is tailored to achieve the catalytic speedup. Finally, an organocatalytic Michael addition, with intriguing selectivity profile, is studied. We propose a detailed catalytic cycle based on DFT calculations to explain the product ratios. The application of the the accessed precursor briefly returns to the realm of biochemistry as we study peptidic foldamer structures using NMR experimental data