Abstract
Linear chains with intra-chain contacts can adopt different topologies and allow transitions between them, but it remains unclear how this process can be controlled. This question is important to systems ranging from proteins to chromosomes, which can adopt different conformations that are key to their function and toxicity. Here, we investigate how the topological dynamics of a simple linear chain is affected by interactions with a binding partner, using Monte Carlo and Molecular Dynamics simulations. We show that two point contacts with a binding partner are sufficient to accelerate or decelerate the formation of particular topologies within linear chains. Computed ''folding-time landscapes" that detail the folding time within the topology space show that such contacts deform these landscapes and hence alter the occupation probability of topological states. The results provide a mechanism by which chain topologies can be controlled externally, which opens up the possibility of regulating topological dynamics and the formation of more complex topologies. The findings may have important implications for understanding the mechanism of chaperone action as well as genome architecture and evolution.
Highlights
Linear chains with intra-chain contacts can adopt different topologies and allow transitions between them, but it remains unclear how this process can be controlled
We investigate how a simple interacting molecule guides folding of client polymer chains toward certain topological states and away from others, and how it modulates the kinetics of folding
We design three simple modeling experiments: (I) an interacting molecule perturbs one of the native intra-chain contacts of the client during folding, by increasing or decreasing the binding affinity of the contact sites; (II) an interacting molecule closes a random loop on its folding substrate which does not exist in the native state; (III) an interacting molecule interferes with client folding by end-to-end cyclization of a linear client polymer chain or by closing a half loop on a partially folded substrate
Summary
Mechanism/molecule which promotes or hinders specific foldimers or pathway. For instance, molecular chaperones recognize and shield exposed hydrophobic residues of folding protein clients and thereby prevent the specific folding pathways of the protein.[2]. We design three simple modeling experiments: (I) an interacting molecule perturbs one of the native intra-chain contacts of the client during folding, by increasing or decreasing the binding affinity of the contact sites (see Fig. 1b); (II) an interacting molecule closes a random loop on its folding substrate which does not exist in the native state (see Fig. 1c); (III) an interacting molecule interferes with client folding by end-to-end cyclization of a linear client polymer chain or by closing a half loop on a partially folded substrate (see Fig. 1d) To this end, we perform Kinetic Monte Carlo (KMC) simulations of a linear Gaussian chain to analyze the folding kinetics and use Molecular Dynamic (MD) simulations for population analysis of topological arrangements in the presence and absence of an interacting molecule. The excluded volume interaction is not present in the KMC simulations which makes its outcome difficult to compare with the steric-mediated folding processes of a real biopolymer, such a simple model is able to provide insights into the configurational entropy, topological occupancy, and kinetic pathways of the constrained chain relative to a free chain.[15,16] through integrating these complementary approaches, we endeavor to contextualize the role of an external interacting molecule in modulating the circuit topology of the folding chain and regulating its folding kinetics
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