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. 2022 Sep 7;54(9):1332–1344. doi: 10.1038/s41588-022-01165-1

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© The Author(s) 2022

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. 6 — a, ACTN3 is a homodimer of two antiparallel filaments, with each filament consisting of an N-terminal actin binding domain (ABD, blue), followed by a structural region comprised of four spectrin repeats (gray) with a C-terminal calmodulin (CAM) homology domain (cyan). b, The glutamate residue side chain in position 635 of ACTN3 (p.Glu635) interacts primarily with the arginine in position 638 and the glutamine in position 639. c, The α-helix comprised of residues adjacent to ACTN3 residue 635 (ACTN2 628) exhibits a pronounced kink in ACTN2 (green) at this α-helical turn compared with ACTN3 p.Glu635 (blue) and p.635Ala (orange), decreasing the likelihood of interactions under load with R631, whereas the alanine substitution of ACTN3 p.635Ala precludes any side chain interactions with neighboring residues p.Arg638 or p.Glu639. d, The r.m.s.f. of the spectrin repeat structural region of the ACTN3 dimer for a 150 ns MD simulation for variants p.Glu635 (blue) and p.635Ala (orange, higher MVPA) and ACTN2 (green) (bottom), with the difference in r.m.s.f. between ACTN3 variants shown mapped to the spectrin repeat region (top) with ±0.3 nm difference (red, positive and blue, negative). e, Umbrella sampling of ACTN3 variants p.Glu635 and p.635Ala and ACTN2 with orange, blue and green traces representing the potential of mean force for ACTN3 variants p.635Ala (orange) and p.Glu635 (blue) and ACTN2 (green) ±1 s.d. The reaction coordinate is the distance between the two ABD centers of mass of each dimer, a negative value indicating a shorter distance between the two ABDs. Inset shows the relaxed dimer at reaction coordinate of 0 nm (top) and the direction and effect on the compressive force. f, Single fiber experiments show a higher maximal force and fiber power during isotonic contractions after an eccentric exercise bout in type II_A fibers from an individual homozygous for p.Arg577 and p.Glu635 (blue) compared with type II_A fibers from three p.Arg577 homozygous, p.Glu635Ala heterozygous individuals (orange); and from four p.577Ter homozygous individuals (green).