Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle

Hartman, Emily C.; Jakobson, Christopher M.; Favor, Andrew H.; Lobba, Marco J.; Álvarez-Benedicto, Ester; Francis, Matthew B.; Tullman-Ercek, Danielle

doi:10.1038/s41467-018-03783-y

Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle

Journal Article · Wed Apr 11 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-03783-y· OSTI ID:1624088

Hartman, Emily C. ^[1]; Jakobson, Christopher M. ^[2]; Favor, Andrew H. ^[3]; Lobba, Marco J. ^[3]; Álvarez-Benedicto, Ester ^[3]; Francis, Matthew B. ^[4]; Tullman-Ercek, Danielle ^[5]

Univ. of California, Berkeley, CA (United States). Dept. of Chemistry; University of California, Berkeley
Univ. of California, Berkeley, CA (United States). Dept. of Chemical and Biomolecular Engineering
Univ. of California, Berkeley, CA (United States). Dept. of Chemistry
Univ. of California, Berkeley, CA (United States). Dept. of Chemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Materials Sciences Division
Northwestern Univ., Evanston, IL (United States). Dept. of Chemical and Biomedical Engineering

Self-assembling proteins are critical to biological systems and industrial technologies, but predicting how mutations affect self-assembly remains a significant challenge. Here, we report a technique, termed SyMAPS (Systematic Mutation and Assembled Particle Selection), that can be used to characterize the assembly competency of all single amino acid variants of a self-assembling viral structural protein. SyMAPS studies on the MS2 bacteriophage coat protein revealed a high-resolution fitness landscape that challenges some conventional assumptions of protein engineering. An additional round of selection identified a previously unknown variant (CP[T71H]) that is stable at neutral pH but less tolerant to acidic conditions than the wild-type coat protein. The capsids formed by this variant could be more amenable to disassembly in late endosomes or early lysosomes—a feature that is advantageous for delivery applications. In addition to providing a mutability blueprint for virus-like particles, SyMAPS can be readily applied to other self-assembling proteins.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Materials Sciences & Engineering Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1624088

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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