Local motifs of disordered proteins: crystal structure, simulations, computations

Rostislav Skrabana¹, Katarina Martonova¹, Ondrej Cehlar¹, Michal Hricovini², Milos Hricovini², Klaudia Meskova¹

¹Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia

²Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia

rostislav.skrabana@savba.sk

In water solution, intrinsically disordered proteins (IDPs) contain no stable three-dimensional structure. IDP’s polypeptide chain is fully hydrated and its conformations are composing a conformational ensemble (CE). Individual conformational states of CE are separated by a small energy barrier and freely interconvert [1].

The structure of globular proteins contains large number of intramolecular hydrogen bonds involving main-chain atoms and resulting in large-scale structural elements of beta sheets and alpha helices. In contrast, IDPs satisfy hydrogen-bonding potential of their main chain almost exclusively by hydrogen bonding to the solvent molecules.

We found that there may be exemptions to this general pattern of H-bonding in IDPs. Starting from the observation of crystal structures and molecular simulations, we proved the existence of intramolecular H-bonds in IDPs. These particular bonds are confined locally and create small 9-15 membered ring structures. Results of simulations indicate that these rings may be stable only for a short period of time and frequently renew their existence. Quantum mechanics calculations revealed the proportion of rings in the local CE.

For these structures we coined the name SPuRs – side chain propelled rings. It is hypothesized that these small ring structures may influence the composition of IDP CE and regulate corresponding biological activity. We have observed several SPURS in crystals of IDP tau with monoclonal antibodies [2]. In the future work we aim to examine the SPURS also in other IDPs.

1. Thomasen FE, Lindorff-Larsen K. Conformational ensembles of intrinsically disordered proteins and flexible multidomain proteins. Biochem Soc Trans. 2022 Feb 28;50(1):541-554. doi: 10.1042/BST20210499. PMID: 35129612.

2. Cehlar O, Bagarova O, Hornakova L, Skrabana R. The structure of the unstructured: mosaic of tau protein linear motifs obtained by high-resolution techniques and molecular simulation. Gen Physiol Biophys. 2021 Nov;40(6):479-493. doi: 10.4149/gpb_2021031. PMID: 34897022.

This work was supported by the grant number APVV-21-0479.