De novo design of pH-responsive self-assembling helical protein filaments

Author:

Shen HaoORCID,Lynch Eric M.ORCID,Akkineni SusrutORCID,Watson Joseph L.,Decarreau Justin,Bethel Neville P.ORCID,Benna Issa,Sheffler William,Farrell Daniel,DiMaio Frank,Derivery Emmanuel,De Yoreo James J.ORCID,Kollman Justin,Baker DavidORCID

Abstract

AbstractBiological evolution has led to precise and dynamic nanostructures that reconfigure in response to pH and other environmental conditions. However, designing micrometre-scale protein nanostructures that are environmentally responsive remains a challenge. Here we describe the de novo design of pH-responsive protein filaments built from subunits containing six or nine buried histidine residues that assemble into micrometre-scale, well-ordered fibres at neutral pH. The cryogenic electron microscopy structure of an optimized design is nearly identical to the computational design model for both the subunit internal geometry and the subunit packing into the fibre. Electron, fluorescent and atomic force microscopy characterization reveal a sharp and reversible transition from assembled to disassembled fibres over 0.3 pH units, and rapid fibre disassembly in less than 1 s following a drop in pH. The midpoint of the transition can be tuned by modulating buried histidine-containing hydrogen bond networks. Computational protein design thus provides a route to creating unbound nanomaterials that rapidly respond to small pH changes.

Funder

Howard Hughes Medical Institute

The Audacious Project at the Institute for Protein Design

United States Department of Defense | Defense Advanced Research Projects Agency

U.S. Department of Energy

Alfred P. Sloan Foundation

National Science Foundation

the Nordstrom Barrier Institute for Protein Design Directors Fund

Human Frontier Science Program

Eric and Wendy Schmidt by recommendation of the Schmidt Futures Program

RCUK | Medical Research Council

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

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