1,813 research outputs found
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 , corresponding
to the perturbation off-criticality, in the {\it logarithmic
limit\,} , where are coprime and the
limit is taken through coprime values of . We view these off-critical
minimal models 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 corresponding to the perturbation of the critical
logarithmic minimal models . 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 . We also calculate the logarithmic limit of certain off-critical
observables related to One Point Functions and show that the
associated critical exponents
produce all conformal dimensions in the infinitely extended Kac table. The corresponding Kac labels
satisfy . The exponent is obtained from the logarithmic limit of the free energy giving the
conformal dimension for the perturbing field . As befits a non-unitary
theory, some observables 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
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