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Related Experiment Video

Updated: May 25, 2025

Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues

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Local structural flexibility drives oligomorphism in computationally designed protein assemblies.

Alena Khmelinskaia^1,2,3,4,5, Neville P Bethel^6,7, Farzad Fatehi^8,9

¹Department of Biochemistry, University of Washington, Seattle, WA, USA. akhmelin@cup.lmu.de.

Nature Structural & Molecular Biology

|February 26, 2025

Summary

This summary is machine-generated.

Computational protein design can now create dynamic protein assemblies by incorporating subunit flexibility. This approach allows for diverse structures, expanding the possibilities for novel protein functions and applications in protein engineering.

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Area of Science:

Protein engineering and structural biology
Computational design of protein assemblies
Biophysics and molecular dynamics

Background:

Naturally occurring protein assemblies often possess dynamic structures essential for their functions.
Current computational protein design methods predominantly focus on creating static protein structures.
There is a need to explore dynamic design principles for novel protein assemblies.

Purpose of the Study:

To characterize computationally designed protein assemblies with inherent subunit flexibility.
To investigate how subunit flexibility influences the structural diversity and stability of designed protein assemblies.
To demonstrate structural flexibility as a viable design principle for protein assembly engineering.

Main Methods:

Cryo-electron microscopy (Cryo-EM) single-particle analysis for high-resolution structure determination.
Native mass spectrometry to assess assembly states and heterogeneity.
Computational modeling, including structural modeling and molecular dynamics simulations, to understand flexibility-driven dynamics.

Main Results:

Three distinct computationally designed protein assemblies were analyzed, revealing unexpected structural diversity.
Two assemblies adopted two distinct architectures, while a third exhibited at least six different structures in solution.
Constrained flexibility within subunits was shown to guide assembly into defined architectures, preventing nonspecific aggregation.
Modifying a flexible region in one protein subunit successfully restored the intended monomorphic assembly.

Conclusions:

Structural flexibility is a powerful and underutilized principle in the computational design of protein assemblies.
Incorporating flexibility allows for the exploration of a broader range of structural and functional possibilities in protein design.
This work advances the field of de novo protein design by enabling the creation of dynamic and functionally versatile protein assemblies.