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Damsbo A, Burlet NJ, Fernández-Quintero ML, Benard-Valle M, Overath MD, Guadarrama-Martínez A, Vlamynck A, Bisbo I, Villalobos C, Tulika T, Alagón A, Loeffler JR, Ward AB, Boddum K, Morth JP, Rivera-de-Torre E, Laustsen AH.
Sun J, Jo G, Troxell CA, Fu Y, Hoezl R, Lv H, Abozeid HH, Teo QW, Pholcharee T, McGrath JJC, Changrob S, Nelson SA, Yasuhara A, Huang M, Zheng NY, Chervin JC, Li L, Fernández-Quintero ML, Loeffler JR, Rodriguez AJ, Huang J, Swanson OM, Balmaseda A, Kuan G, Campredon L, Allen EK, Neumann G, Wu NC, Kawaoka Y, Krammer F, Thomas PG, Gordon A, Ward AB, Han J, Wilson PC.
Marini-Rapoport O, Andrieux L, Keswani T, Zong G, Duchen D, Yaari G, Min J, Lytle IR, Rosenberg AF, Fucile C, Kobie JJ, Piepenbrink MS, Sun T, Martin VM, Yuan Q, Shreffler WG, Seppo AE, Järvinen KM, Loeffler JR, Ward AB, Kleinstein SH, Pedersen LC, Fernández-Quintero ML, Mueller GA, Patil SU.
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Khmelinskaia A, Bethel NP, Fatehi F, Mallik BB, Antanasijevic A, Borst AJ, Lai SH, Chim HY, Wang JY', Miranda MC, Watkins AM, Ogohara C, Caldwell S, Wu M, Heck AJR, Veesler D, Ward AB, Baker D, Twarock R, King NP.
Nat Struct Mol Biol
June 1, 2025
Many naturally occurring protein assemblies have dynamic structures that allow them to perform specialized functions. Although computational methods for designing novel self-assembling proteins have advanced substantially over the past decade, they primarily focus on designing static structures. Here we characterize three distinct computationally designed protein assemblies that exhibit unanticipated structural diversity arising from flexibility in their subunits. Cryo-EM single-particle reconstructions and native mass spectrometry reveal two distinct architectures for two assemblies, while six cryo-EM reconstructions for the third likely represent a subset of its solution-phase structures. Structural modeling and molecular dynamics simulations indicate that constrained flexibility within the subunits of each assembly promotes a defined range of architectures rather than nonspecific aggregation. Redesigning the flexible region in one building block rescues the intended monomorphic assembly. These findings highlight structural flexibility as a powerful design principle, enabling exploration of new structural and functional spaces in protein assembly design.