RosettaDDGPrediction for high‐throughput mutational scans: From stability to binding

Reliable prediction of free energy changes upon amino acid substitutions (ΔΔGs) is crucial to investigate their impact on protein stability and protein–protein interaction. Advances in experimental mutational scans allow high‐throughput studies thanks to multiplex techniques. On the other hand, geno...

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Veröffentlicht in:Protein science 2023-01, Vol.32 (1), p.e4527-n/a
Hauptverfasser: Sora, Valentina, Laspiur, Adrian Otamendi, Degn, Kristine, Arnaudi, Matteo, Utichi, Mattia, Beltrame, Ludovica, De Menezes, Dayana, Orlandi, Matteo, Stoltze, Ulrik Kristoffer, Rigina, Olga, Sackett, Peter Wad, Wadt, Karin, Schmiegelow, Kjeld, Tiberti, Matteo, Papaleo, Elena
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container_issue 1
container_start_page e4527
container_title Protein science
container_volume 32
creator Sora, Valentina
Laspiur, Adrian Otamendi
Degn, Kristine
Arnaudi, Matteo
Utichi, Mattia
Beltrame, Ludovica
De Menezes, Dayana
Orlandi, Matteo
Stoltze, Ulrik Kristoffer
Rigina, Olga
Sackett, Peter Wad
Wadt, Karin
Schmiegelow, Kjeld
Tiberti, Matteo
Papaleo, Elena
description Reliable prediction of free energy changes upon amino acid substitutions (ΔΔGs) is crucial to investigate their impact on protein stability and protein–protein interaction. Advances in experimental mutational scans allow high‐throughput studies thanks to multiplex techniques. On the other hand, genomics initiatives provide a large amount of data on disease‐related variants that can benefit from analyses with structure‐based methods. Therefore, the computational field should keep the same pace and provide new tools for fast and accurate high‐throughput ΔΔG calculations. In this context, the Rosetta modeling suite implements effective approaches to predict folding/unfolding ΔΔGs in a protein monomer upon amino acid substitutions and calculate the changes in binding free energy in protein complexes. However, their application can be challenging to users without extensive experience with Rosetta. Furthermore, Rosetta protocols for ΔΔG prediction are designed considering one variant at a time, making the setup of high‐throughput screenings cumbersome. For these reasons, we devised RosettaDDGPrediction, a customizable Python wrapper designed to run free energy calculations on a set of amino acid substitutions using Rosetta protocols with little intervention from the user. Moreover, RosettaDDGPrediction assists with checking completed runs and aggregates raw data for multiple variants, as well as generates publication‐ready graphics. We showed the potential of the tool in four case studies, including variants of uncertain significance in childhood cancer, proteins with known experimental unfolding ΔΔGs values, interactions between target proteins and disordered motifs, and phosphomimetics. RosettaDDGPrediction is available, free of charge and under GNU General Public License v3.0, at https://github.com/ELELAB/RosettaDDGPrediction.
doi_str_mv 10.1002/pro.4527
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subjects Amino acid sequence
Amino acids
Binding
binding free energy
Case studies
Children
Computer applications
Entropy
folding free energy
Free energy
free energy calculations
Mutation
Protein folding
Protein Stability
Proteins
Proteins - chemistry
Rosetta
Software
Stability
Tools for Protein Science
title RosettaDDGPrediction for high‐throughput mutational scans: From stability to binding
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