Biology subjects

Hellemann, E.

Publications and source records attributed to Hellemann, E..

3 recordsLinked to original sources

bioRxiv2023

Worth the weight: Sub-Pocket EXplorer (SubPEx), a weighted-ensemble method to enhance binding-pocket conformational sampling

1.Structure-based virtual screening (VS) is an effective method for identifying potential small-molecule ligands, but traditional VS approaches consider only a single binding-pocket conformation. Consequently, they struggle to identify ligands that bind to alternate conformations. Ensemble docking helps address this issue by incorporating multiple conformations into the docking process, but it depends on methods that can thoroughly explore pocket flexibility. We here introduce Sub-Pocket EXplorer (SubPEx), an approach that uses weighted ensemble (WE) path sampling to accelerate binding-pocket sampling. As proof of principle, we apply SubPEx to three proteins relevant to drug discovery: heat shock protein 90, influenza neuraminidase, and yeast hexokinase 2. SubPEx is available free of charge without registration under the terms of the open-source MIT license: http://durrantlab.com/subpex/

bioinformatics↗

bioRxiv2021

Defining the Yeast Resistome through in vitro Evolution and Whole Genome Sequencing

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in the model microbe, Saccharomyces cerevisiae. Analysis of 355 curated, laboratory-evolved clones, resistant to 80 different compounds, demonstrates differences in the types of mutations that are identified in selected versus neutral evolution and reveals numerous new, compound-target interactions. Through enrichment analysis we further identify a set of 137 genes strongly associated with or conferring drug resistance as indicated by CRISPR-Cas9 engineering. The set of 25 most frequently mutated genes was enriched for transcription factors and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function, single nucleotide variants found in 170-amino-acid domains in two Zn2C6 transcription factors, YRR1 and YRM1 (p < 1x 10 -100). This remarkable enrichment for transcription factors as drug resistance genes may explain why it is challenging to develop effective antifungal killing agents and highlights their important role in evolution.

genetics↗

bioRxiv2019

Webina: An Open-Source Library and Web App that Runs AutoDock Vina Entirely in the Web Browser

1Molecular docking is a computational technique for predicting how a small molecule might bind a macromolecular target. Among docking programs, AutoDock Vina is particularly popular. Like many docking programs, Vina requires users to download/install an executable file and to run that file from a Unix- or DOS-like command-line interface. Choosing proper configuration parameters and analyzing Vina output is also sometimes challenging. These issues are particularly problematic for students and novice researchers. We have created Webina, a new version of Vina, to address these challenges. Webina is a JavaScript/WebAssembly library that runs AutoDock Vina entirely in a web browser. To use Webina, users need only visit a Webina-enabled webpage. The docking calculations take place on the users own computer rather than a remote server. To encourage use, we have incorporated the Webina library into our own Webina web app. The app includes a convenient interface so users can easily setup their docking runs and analyze the results. Webina will be a useful open-source tool for the research and educational communities. A working version of the app can be accessed free of charge from http://durrantlab.com/webina.

pharmacology and toxicology↗