A Suite of Designed Protein Cages Using Machine Learning and Protein Fragment-based Protocols

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2024 Mar 21

PMID 38513658

Authors

Kyle Meador

Roger Castells-Graells

Roman Aguirre

Michael R Sawaya

Mark A Arbing

Trent Sherman

Chethaka Senarathne

Todd O Yeates

Affiliations

Soon will be listed here.

Abstract

Designed protein cages and related materials provide unique opportunities for applications in biotechnology and medicine, but their creation remains challenging. Here, we apply computational approaches to design a suite of tetrahedrally symmetric, self-assembling protein cages. For the generation of docked conformations, we emphasize a protein fragment-based approach, while for sequence design of the de novo interface, a comparison of knowledge-based and machine learning protocols highlights the power and increased experimental success achieved using ProteinMPNN. An analysis of design outcomes provides insights for improving interface design protocols, including prioritizing fragment-based motifs, balancing interface hydrophobicity and polarity, and identifying preferred polar contact patterns. In all, we report five structures for seven protein cages, along with two structures of intermediate assemblies, with the highest resolution reaching 2.0 Å using cryo-EM. This set of designed cages adds substantially to the body of available protein nanoparticles, and to methodologies for their creation.

Citing Articles

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