Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis

Aim: Molecular dynamics simulations and normal mode analysis are well-established approaches to generate receptor conformational ensembles (RCEs) for ligand docking and virtual screening. Here, we report new fast molecular dynamics-based and normal mode analysis-based protocols combined with conformational pocket classifications to efficiently generate RCEs. Materials \& methods: We assessed our protocols on two well-characterized protein targets showing local active site flexibility, dihydrofolate reductase and large collective movements, CDK2. The performance of the RCEs was validated by distinguishing known ligands of dihydrofolate reductase and CDK2 among a dataset of diverse chemical decoys. Results \& discussion: Our results show that different simulation protocols can be efficient for generation of RCEs depending on different kind of protein flexibility

Closed form solution for a double quantum well using Gr\"obner basis

Analytical expressions for spectrum, eigenfunctions and dipole matrix elements of a square double quantum well (DQW) are presented for a general case when the potential in different regions of the DQW has different heights and effective masses are different. This was achieved by Gr\"obner basis algorithm which allows to disentangle the resulting coupled polynomials without explicitly solving the transcendental eigenvalue equation.Comment: 4 figures, Mathematica full calculation noteboo

The Initial Mass Function in disc galaxies and in galaxy clusters: the chemo-photometric picture

The observed brightness of the Tully-Fisher relation suggests a low stellar M/L ratio and a "bottom-light" IMF in disc galaxies, but the corresponding efficiency of chemical enrichment tends to exceed the observational estimates. Either suitable tuning of the IMF slope and mass limits or metal outflows from disc galaxies must then be invoked. A standard Solar Neighbourhood IMF cannot explain the high metallicity of the hot intra-cluster medium: a different IMF must be at work in clusters of galaxies. Alternatively, if the IMF is universal and chemical enrichment is everywhere as efficient as observed in clusters, substantial loss of metals must occur from the Solar Neighbourhood and from disc galaxies in general; a "non-standard" scenario challenging our understanding of disc galaxy formation.Comment: 6 pages, 4 figures; in Proceedings of IMF@50: the Initial Mass Function 50 years later; Corbelli, Palla and Zinnecker (eds.

Off-Critical Logarithmic Minimal Models

We consider the integrable minimal models ${\cal M}(m,m';t)$, corresponding to the $\varphi_{1,3}$ perturbation off-criticality, in the {\it logarithmic limit\,} $m, m'\to\infty$, $m/m'\to p/p'$ where $p, p'$ are coprime and the limit is taken through coprime values of $m,m'$. We view these off-critical minimal models ${\cal M}(m,m';t)$ as the continuum scaling limit of the Forrester-Baxter Restricted Solid-On-Solid (RSOS) models on the square lattice. Applying Corner Transfer Matrices to the Forrester-Baxter RSOS models in Regime III, we argue that taking first the thermodynamic limit and second the {\it logarithmic limit\,} yields off-critical logarithmic minimal models ${\cal LM}(p,p';t)$ corresponding to the $\varphi_{1,3}$ perturbation of the critical logarithmic minimal models ${\cal LM}(p,p')$. Specifically, in accord with the Kyoto correspondence principle, we show that the logarithmic limit of the one-dimensional configurational sums yields finitized quasi-rational characters of the Kac representations of the critical logarithmic minimal models ${\cal LM}(p,p')$. We also calculate the logarithmic limit of certain off-critical observables ${\cal O}_{r,s}$ related to One Point Functions and show that the associated critical exponents $\beta_{r,s}=(2-\alpha)\,\Delta_{r,s}^{p,p'}$ produce all conformal dimensions $\Delta_{r,s}^{p,p'}<{(p'-p)(9p-p')\over 4pp'}$ in the infinitely extended Kac table. The corresponding Kac labels $(r,s)$ satisfy $(p s-p' r)^2< 8p(p'-p)$. The exponent $2-\alpha ={p'\over 2(p'-p)}$ is obtained from the logarithmic limit of the free energy giving the conformal dimension $\Delta_t={1-\alpha\over 2-\alpha}={2p-p'\over p'}=\Delta_{1,3}^{p,p'}$ for the perturbing field $t$. As befits a non-unitary theory, some observables ${\cal O}_{r,s}$ diverge at criticality.Comment: 18 pages, 5 figures; version 3 contains amplifications and minor typographical correction

Galactic Collapse of Scalar Field Dark Matter

We present a scenario for galaxy formation based on the hypothesis of scalar field dark matter. We interpret galaxy formation through the collapse of a scalar field fluctuation. We find that a cosh potential for the self-interaction of the scalar field provides a reasonable scenario for galactic formation, which is in agreement with cosmological observations and phenomenological studies in galaxies.Comment: 4 pages, 3 figue

Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates

Computational drug design based on artificial intelligence is an emerging research area. At the time of writing this paper, the world suffers from an outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus replication is via protease inhibition. We propose an evolutionary multi-objective algorithm (EMOA) to design potential protease inhibitors for SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA maximizes the binding of candidate ligands to the protein using the docking tool QuickVina 2, while at the same time taking into account further objectives like drug-likeliness or the fulfillment of filter constraints. The experimental part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202

Gridded and direct Epoch of Reionisation bispectrum estimates using the Murchison Widefield Array

We apply two methods to estimate the 21~cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly-spaced triangles of antenna tiles, as well as an estimate based on data gridded to the $uv$-plane. The direct and gridded bispectrum estimators are applied to 21 hours of high-band (167--197~MHz; $z$=6.2--7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 hours, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21~cm bispectrum may be accessible in less time than the 21~cm power spectrum for some wave modes, with detections in hundreds of hours.Comment: 19 pages, 10 figures, accepted for publication in PAS

Second order QCD corrections to inclusive semileptonic b \to Xc l \bar \nu_l decays with massless and massive lepton

We extend previous computations of the second order QCD corrections to semileptonic b \to c inclusive transitions, to the case where the charged lepton in the final state is massive. This allows accurate description of b \to c \tau \bar \nu_\tau decays. We review techniques used in the computation of O(\alpha_s^2) corrections to inclusive semileptonic b \to c transitions and present extensive numerical studies of O(\alpha_s^2) QCD corrections to b \to c l \bar \nu_l decays, for l =e, \tau.Comment: 30 pages, 4 figures, 5 table

New Physics Models of Direct CP Violation in Charm Decays

In view of the recent LHCb measurement of Delta A_CP, the difference between the time-integrated CP asymmetries in D --> K+K- and D --> pi+pi- decays, we perform a comparative study of the possible impact of New Physics degrees of freedom on the direct CP asymmetries in singly Cabibbo suppressed D meson decays. We systematically discuss scenarios with a minimal set of new degrees of freedom that have renormalizable couplings to the SM particles and that are heavy enough such that their effects on the D meson decays can be described by local operators. We take into account both constraints from low energy flavor observables, in particular D0-D0bar mixing, and from direct searches. While models that explain the large measured value for Delta A_CP with chirally enhanced chromomagnetic penguins are least constrained, we identify a few viable models that contribute to the D meson decays at tree level or through loop induced QCD penguins. We emphasize that such models motivate direct searches at the LHC.Comment: 24 pages, 13 figures. v2: typos corrected, reference added, published versio

Virtual screening for inhibitors of the human TSLP:TSLPR interaction

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation