# Deceptive beauty of non‐natural structures

## TL;DR

Protein structures often reflect non-natural conditions and may not fully represent their real-world function.

## Contribution

Highlights the limitations of structural data in capturing true protein dynamics and function.

## Key findings

- Structures solved under nonphysiological conditions may not align with functional data.
- Protein dynamics are not fully captured by static structures or simulations alone.
- Combining multiple methods is essential to understand protein mechanisms in natural environments.

## Abstract

Structures of proteins and multiprotein complexes are considered landmark achievements. However, in many cases, mutant proteins are used for structural work. Even when wild type proteins are used, crystallization or complex formation for cryoEM is performed in highly nonphysiological conditions. This explains why the structures can be inconsistent with the functional data. The structures are always true, but solved structures faithfully reveal the mode of interactions of the proteins used in the conditions employed. The structures are static, whereas proteins are dynamic. Even when a series of structures are solved, the dynamics are only implied or deduced via molecular dynamics simulations. The mechanisms of protein function in the natural environment can be revealed by the combination of structural, biochemical, biophysical, and in vivo studies, supplemented by molecular modeling.