Computational design of a sensitive, selective phase-changing sensor protein for the VX nerve agent

Author:

McCann James J.1ORCID,Pike Douglas H.2,Brown Mia C.1ORCID,Crouse David T.3,Nanda Vikas2ORCID,Koder Ronald L.14ORCID

Affiliation:

1. Department of Physics, The City College of New York, New York, NY 10031, USA.

2. Center for Advanced Biotechnology and Medicine and the Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.

3. Department of Electrical and Computer Engineering, Clarkson University, Potsdam, NY 13699, USA.

4. Graduate Programs of Physics, Biology, Chemistry, and Biochemistry, The Graduate Center of CUNY, New York, NY 10016, USA.

Abstract

The VX nerve agent is one of the deadliest chemical warfare agents. Specific, sensitive, real-time detection methods for this neurotoxin have not been reported. The creation of proteins that use biological recognition to fulfill these requirements using directed evolution or library screening methods has been hampered because its toxicity makes laboratory experimentation extraordinarily expensive. A pair of VX-binding proteins were designed using a supercharged scaffold that couples a large-scale phase change from unstructured to folded upon ligand binding, enabling fully internal binding sites that present the maximum surface area possible for high affinity and specificity in target recognition. Binding site residues were chosen using a new distributed evolutionary algorithm implementation in protCAD. Both designs detect VX at parts per billion concentrations with high specificity. Computational design of fully buried molecular recognition sites, in combination with supercharged phase-changing chassis proteins, enables the ready development of a new generation of small-molecule biosensors.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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