Abstract
Molecular dynamics simulations are used to explore the effects of chaperonin-like cages on knotted proteins with very low sequence similarity, different depths of a knot but with a similar fold, and the same type of topology. The investigated proteins are VirC2, DndE and MJ0366 with two depths of a knot. A comprehensive picture how encapsulation influences folding rates is provided based on the analysis of different cage sizes and temperature conditions. Neither of these two effects with regard to knotted proteins has been studied by means of molecular dynamics simulations with coarse-grained structure-based models before. We show that encapsulation in a chaperonin is sufficient to self-tie and untie small knotted proteins (VirC2, DndE), for which the equilibrium process is not accessible in the bulk solvent. Furthermore, we find that encapsulation reduces backtracking that arises from the destabilisation of nucleation sites, smoothing the free energy landscape. However, this effect can also be coupled with temperature rise. Encapsulation facilitates knotting at the early stage of folding and can enhance an alternative folding route. Comparison to unknotted proteins with the same fold shows directly how encapsulation influences the free energy landscape. In addition, we find that as the size of the cage decreases, folding times increase almost exponentially in a certain range of cage sizes, in accordance with confinement theory and experimental data for unknotted proteins.
Highlights
The majority of small globular proteins can fold spontaneously in the cellular environment
We find that encapsulation smoothens the free energy landscape and eliminates kinetic traps by reducing backtracking that arises from the destabilisation of nucleation sites
In this work we examined the influence of confinement on entanglement probability, foldingunfolding rates, knotting pathways and in consequence on the shape of the free energy landscape of four knotted proteins with various depths of knots, sequences and folds
Summary
The majority of small globular proteins can fold spontaneously in the cellular environment. To ensure folding of complex proteins and prevent them from aggregation, in each of the domains of life so-called chaperone networks emerged [1]. The most universal molecular chaperones are chaperonins. They form a specialised nano-compartment for single protein molecules to allow folding in isolation [2,3,4]. Recent data suggest that the chaperonin may actively rescue proteins from kinetic folding traps, thereby accelerating their folding rates [5, 6]. Knotted bacterial proteins [7] represent a class of proteins which could significantly benefit from chaperonins.
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