The serpin plasminogen activator inhibitor 1 (PAI-1) spontaneously undergoes a massive structural change from a metastable and active conformation, with a solvent-accessible reactive center loop ...(RCL), to a stable, inactive, or latent conformation, with the RCL inserted into the central β-sheet. Physiologically, conversion to the latent state is regulated by the binding of vitronectin, which hinders the latency transition rate approximately twofold. The molecular mechanisms leading to this rate change are unclear. Here, we investigated the effects of vitronectin on the PAI-1 latency transition using all-atom path sampling simulations in explicit solvent. In simulated latency transitions of free PAI-1, the RCL is quite mobile as is the gate, the region that impedes RCL access to the central β-sheet. This mobility allows the formation of a transient salt bridge that facilitates the transition; this finding rationalizes existing mutagenesis results. Vitronectin binding reduces RCL and gate mobility by allosterically rigidifying structural elements over 40 Å away from the binding site, thus blocking transition to the latent conformation. The effects of vitronectin are propagated by a network of dynamically correlated residues including a number of conserved sites that were previously identified as important for PAI-1 stability. Simulations also revealed a transient pocket populated only in the vitronectin-bound state, corresponding to a cryptic drug-binding site identified by crystallography. Overall, these results shed new light on PAI-1 latency transition regulation by vitronectin and illustrate the potential of path sampling simulations for understanding functional protein conformational changes and for facilitating drug discovery.
This open-access book addresses the following questions: how does the polarization of a particle, i.e., the angular momentum state in which it is produced, manifest itself in nature? What are the ...concepts and tools needed to perform rigorous measurements providing complete and unambiguous physical information? Polarization measurements are important because they reflect the nature and coupling properties of a particle and provide unique insights into the underlying fundamental interactions, playing a central role in the study and understanding of the mechanisms of particle production. Besides gradually reviewing many fundamental notions, the book presents several case studies relevant to physics analyses underway at the LHC, including the lepton-antilepton decays of vector states (Drell–Yan, Z and W bosons, quarkonia, etc.). The book also offers a detailed discussion of cascade decays, where the vector particle is a daughter of another particle, as well as a survey of typical angular distributions of particles of any integer or half-integer spin. With a visual approach to the presentation of the concepts and frequent use of pedagogical examples, taken from real measurements, gedankenexperiments, or detailed simulations, the book focuses on aspects of polarization measurements that are sometimes underestimated or left unexplored in experimental analyses, such as the importance of the choice of the reference frame, the existence of frame-independent relations, and the shapes of the physically allowed parameter domains. Several examples are provided of pitfalls introduced when the intrinsic multidimensionality of the problem is neglected in exchange for a simplified analysis. Targeting an audience of graduate students, post-docs, and other researchers involved in analyses of LHC data, this book helps to establish a solid bridge between high precision data, existing or soon to be collected, and accurate measurements, including high-sensitivity tests of the Standard Model.
The dominant reaction pathway (DRP) is an algorithm to microscopically compute the most probable reaction pathways in the overdamped Langevin dynamics without investing computational time in ...simulating the local thermal motion in the metastable configurations. In order to test the accuracy of such a method, we investigate the dynamics of the folding of a beta hairpin within a model that accounts for both native and non-native interactions. We compare the most probable folding pathways calculated with the DRP method with the folding trajectories obtained directly from molecular dynamics simulations. We find that the two approaches give consistent results.
We report on the status of the CMS experiment and on plans for spin physics measurements at the LHC. We focus on the short-term prospect of quarkonium polarization studies, which promise to solve ...longstanding puzzles on non-perturbative aspects of QCD.
Protein misfolding is implicated in many diseases, including serpinopathies. For the canonical inhibitory serpin α1-antitrypsin, mutations can result in protein deficiencies leading to lung disease, ...and misfolded mutants can accumulate in hepatocytes, leading to liver disease. Using all-atom simulations based on the recently developed bias functional algorithm, we elucidate how wild-type α1-antitrypsin folds and how the disease-associated S (Glu264Val) and Z (Glu342Lys) mutations lead to misfolding. The deleterious Z mutation disrupts folding at an early stage, whereas the relatively benign S mutant shows late-stage minor misfolding. A number of suppressor mutations ameliorate the effects of the Z mutation, and simulations on these mutants help to elucidate the relative roles of steric clashes and electrostatic interactions in Z misfolding. These results demonstrate a striking correlation between atomistic events and disease severity and shine light on the mechanisms driving chains away from their correct folding routes.
The covariance properties of angular momentum eigenstates imply the existence of a rotation-invariant relation among the parameters of the difermion decay distribution of inclusively observed vector ...mesons. This relation is a generalization of the Lam-Tung identity, a result specific to Drell-Yan production in perturbative QCD, here shown to be equivalent to the dynamical condition that the dilepton is always produced transversely polarized with respect to quantization axes belonging to the production plane.
A number of previous successful attempts in the search for therapeutics for a variety of human pathologies highlight the importance of computational technologies in the drug discovery pipeline. This ...approach, often referred to as computer-aided drug design, is unfortunately inapplicable when the precise information regarding the three-dimensional structure of disease-associated proteins or the mechanism by which they are altered to generate misfolded isoforms are missing. A typical example is represented by prion diseases, fatal pathologies of the nervous system characterized by the conformational conversion of a physiological protein called PrPC into a misfolded and infectious isoform referred to as PrPSc. Missing information regarding the atomic structure of PrPSc as well as the mechanism of templated conversion of PrPC has severely halted the discovery of effective therapies for prion diseases. In this manuscript, we review emerging opportunities to apply computer-aided techniques to target PrPC, PrPSc or to design inhibitors of prion replication, and discuss how these fast-evolving technologies could lay the groundwork for the application of entirely novel rational drug design schemes for these devastating pathologies.
Topological phenomena in gauge theories have long been recognized as the driving force for chiral symmetry breaking and confinement. These phenomena can be conveniently investigated in the ...semiclassical picture, in which the topological charge is entirely carried by (anti-)self-dual gauge configurations. In such an approach, it has been shown that near the critical temperature, the nonzero expectation value of the Polyakov loop (holonomy) triggers the "Higgsing" of the color group, generating the splitting of instantons into Nc self-dual dyons. A number of lattice simulations have provided some evidence for such dyons, and traced their relation with specific observables, such as the Dirac eigenvalue spectrum. In this work, we formulate a model, based on one-loop partition function and including Coulomb interaction, screening and fermion zero modes. We then perform the first numerical Monte Carlo simulations of a statistical ensemble of self-dual dyons, as a function of their density, quark mass and the number of flavors. We study different dyonic two-point correlation functions and we compute the Dirac spectrum, as a function of the ensemble diluteness and the number of quark flavors.
A global analysis of ATLAS and CMS measurements reveals that, at mid-rapidity, the directly-produced Formula omitted, Formula omitted and J/ Formula omitted mesons have differential cross sections of ...seemingly identical shapes, when presented as a function of the mass-rescaled transverse momentum, Formula omitted. This identity of kinematic behaviours among S- and P-wave quarkonia is certainly not a natural expectation of non-relativistic QCD (NRQCD), where each quarkonium state is supposed to reflect a specific family of elementary production processes, of significantly different Formula omitted-differential cross sections. Remarkably, accurate kinematic cancellations among the various NRQCD terms (colour singlets and octets) of its factorization expansion can lead to a surprisingly good description of the data. This peculiar tuning of the NRQCD mixtures leads to a clear prediction regarding the Formula omitted and Formula omitted polarizations, the only observables not yet measured: they should be almost maximally different from one another, and from the J/ Formula omitted polarization, a striking exception in the global panorama of quarkonium production. Measurements of the difference between the Formula omitted, Formula omitted and J/ Formula omitted polarizations, complementing the observed identity of momentum dependences, represent a decisive probe of NRQCD.
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