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

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

Challenges in implementing routine cardiopulmonary exercise testing in cystic fibrosis clinical practice: a single centre review

This is the final version. Available on open access from Springer via the DOI in this recordCardiopulmonary exercise testing (CPET) is viewed by many as the gold standard for assessing exercise capacity in CF, being recommended on an annual basis. However, not all patients undergo CPET for varying reasons. This service evaluation retrospectively reviewed data from 179 (92 male) patients in a single CF centre in the UK to identify such reasons. 75/179 patients underwent CPET, whilst 104/179 did not. Of these 104, 41 patients were ≤ 11 years of age. Of the remaining 63 patients, 26 did not undergo CPET for clinical reasons including needing IV antibiotics, musculoskeletal issues and obesity. 17 refused to undergo CPET because of reasons such as an unwillingness to travel and dislike of CPET. 20 did not undergo CPET for miscellaneous reasons including difficulty contacting patients. Individuals with FEV1 <40%predicted were 85.7% less likely to undertake a CPET than individuals with FEV1 ≥70%predicted. Understanding these challenges will assist clinical teams with future implementation of CPET into routine care, by identifying areas for improvement and establishing strategies for enhancing future provision of the test

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.

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

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