In-Cell Protein–Protein Contacts: Transient Interactions in the Crowd

Proteins
in vivo are immersed in a crowded environment of water,
ions, metabolites, and macromolecules. In-cell experiments highlight
how transient weak protein–protein interactions promote (via
functional “quinary structure”) or hinder (via competitive
binding or “sticking”) complex formation. Computational
models of the cytoplasm are expensive. We tackle this challenge with
an all-atom model of a small volume of the E. coli cytoplasm to simulate protein–protein contacts up to the
5 μs time scale on the special-purpose supercomputer Anton 2.
We use three CHARMM-derived force fields: C22*, C36m, and C36mCU (with
CUFIX corrections). We find that both C36m and C36mCU form smaller
contact surfaces than C22*. Although CUFIX was developed to reduce
protein–protein sticking, larger contacts are observed with
C36mCU than C36m. We show that the lifespan Δt of protein–protein contacts obeys a power law distribution
between 0.03 and 3 μs, with ∼90% of all contacts lasting
<1 μs (similar to the time scale for downhill folding).