In silico protein dynamics in the human cytoplasm: Partial folding, misfolding, fold switching, and non‐native interactions

Author:

Russell Premila P. Samuel1ORCID,Rickard Meredith M.1ORCID,Boob Mayank2ORCID,Gruebele Martin1234ORCID,Pogorelov Taras V.12356ORCID

Affiliation:

1. Department of Chemistry University of Illinois Urbana‐Champaign Urbana Illinois USA

2. Center for Biophysics and Quantitative Biology University of Illinois Urbana‐Champaign Urbana Illinois USA

3. Beckman Institute for Advanced Science and Technology University of Illinois at Urbana‐Champaign Urbana Illinois USA

4. Department of Physics University of Illinois Urbana‐Champaign Urbana Illinois USA

5. National Center for Supercomputing Applications University of Illinois Urbana‐Champaign Urbana Illinois USA

6. School of Chemical Sciences University of Illinois Urbana‐Champaign Urbana Illinois USA

Abstract

AbstractWe examine the influence of cellular interactions in all‐atom models of a section of the Homo sapiens cytoplasm on the early folding events of the three‐helix bundle protein B (PB). While genetically engineered PB is known to fold in dilute water box simulations in three microseconds, the three initially unfolded PB copies in our two cytoplasm models using a similar force field did not reach the native state during 30‐microsecond simulations. We did however capture the formation of all three helices in a compact native‐like topology. Folding in vivo is delayed because intramolecular contact formation within PB is in direct competition with intermolecular contacts between PB and surrounding macromolecules. In extreme cases, intermolecular beta‐sheets are formed. Interactions with other macromolecules are also observed to promote structure formation, for example when a PB helix in our simulations is shielded from solvent by macromolecular crowding. Sticking and crowding in our models initiate sampling of helix/sheet structural plasticity of PB. Relatedly, in past in vitro experiments, similar GA domains were shown to switch between two different folds. Finally, we also observed that stickiness between PB and the cellular environment can be modulated in our simulations through the reduction in protein hydrophobicity when we reversed PB back to the wild‐type sequence. This study demonstrates that even fast‐folding proteins can get stuck in non‐native states in the cell, making them useful models for protein–chaperone interactions and early stages of aggregate formation relevant to cellular disease.

Funder

National Institutes of Health

National Science Foundation

Publisher

Wiley

Subject

Molecular Biology,Biochemistry

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