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. 2021 Jun 23;12:3867. doi: 10.1038/s41467-021-23943-x

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — a The pairwise epistatic interaction effects for each metal environment. The two interacting residues are denoted on the x-axis by their positions, with an “x” in between them (e.g., 72 × 193 denote the pair-wise effects of mutations at positions 72 and 193). b The relationship between the effect of mutating position 271 and the number of previously fixed substitutions at other sites for each metal. Symbol (*) denotes a statistically significant correlation (p < 0.05 after correcting for multiple tests). c The impact of previous substitutions at positions 72, 193, 258. and 273 on the effect of the substitution at position 271.