Expanding the space of protein geometries by computational design of de novo fold families

Naturally occurring proteins vary the precise geometries of structural elements to create distinct shapes optimal for function. We present a computational design method, loop-helix-loop unit combinatorial sampling (LUCS), that mimics nature's ability to create families of proteins with the same...

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Published inScience (American Association for the Advancement of Science) Vol. 369; no. 6507; pp. 1132 - 1136
Main Authors Pan, Xingjie, Thompson, Michael C, Zhang, Yang, Liu, Lin, Fraser, James S, Kelly, Mark J S, Kortemme, Tanja
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 28.08.2020
Subjects
Combinatorial analysis
Computer applications
Computer-Aided Design
Custom design
Landscape design
Protein Engineering - methods
Protein Folding
Protein Structure, Secondary
Proteins
Sampling
Structural analysis
Structural Elements (Construction)
Structural members
Topology
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Summary:Naturally occurring proteins vary the precise geometries of structural elements to create distinct shapes optimal for function. We present a computational design method, loop-helix-loop unit combinatorial sampling (LUCS), that mimics nature's ability to create families of proteins with the same overall fold but precisely tunable geometries. Through near-exhaustive sampling of loop-helix-loop elements, LUCS generates highly diverse geometries encompassing those found in nature but also surpassing known structure space. Biophysical characterization showed that 17 (38%) of 45 tested LUCS designs encompassing two different structural topologies were well folded, including 16 with designed non-native geometries. Four experimentally solved structures closely matched the designs. LUCS greatly expands the designable structure space and offers a new paradigm for designing proteins with tunable geometries that may be customizable for novel functions.
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Author contributions: XP conceived the idea for the project. XP and TK conceived the computational and experimental approach. XP developed and performed the computational design. XP and YZ performed the majority of the experimental characterization. XP and MJSK determined the NMR structures. XP, MT, LL and JSF determined the crystal structure. JSF, MJSK and TK provided guidance, mentorship and resources. XP and TK wrote the manuscript with contributions from the other authors.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abc0881