Protein self-entanglement modulates successful folding to the native state: A multi-scale modeling study.

Lorenzo Federico Signorini,Raffaello Potestio,Claudio Perego

doi:10.1063/5.0063254

Abstract

The computer-aided investigation of protein folding has greatly benefited from coarse-grained models, that is, simplified representations at a resolution level lower than atomistic, providing access to qualitative and quantitative details of the folding process that would be hardly attainable, via all-atom descriptions, for medium to long molecules. Nonetheless, the effectiveness of low-resolution models is itself hampered by the presence, in a small but significant number of proteins, of nontrivial topological self-entanglements. Features such as native state knots or slipknots introduce conformational bottlenecks, affecting the probability to fold into the correct conformation; this limitation is particularly severe in the context of coarse-grained models. In this work, we tackle the relationship between folding probability, protein folding pathway, and protein topology in a set of proteins with a nontrivial degree of topological complexity. To avoid or mitigate the risk of incurring in kinetic traps, we make use of the elastic folder model, a coarse-grained model based on angular potentials optimized toward successful folding via a genetic procedure. This light-weight representation allows us to estimate in silico folding probabilities, which we find to anti-correlate with a measure of topological complexity as well as to correlate remarkably well with experimental measurements of the folding rate. These results strengthen the hypothesis that the topological complexity of the native state decreases the folding probability and that the force-field optimization mimics the evolutionary process these proteins have undergone to avoid kinetic traps.

Highlights

Since the discovery of the first knotted native structure in 1994,1 a large number of proteins has been found to entail some degree of topological complexity.2–5 According to KnotProt,6 at present over 1600 proteins are known that feature one of the various kinds of possible topological motifs:2,6,7 these can be knots,1,3,4,8,9 slipknots,4,10 complex lassos,11,12 or links.2 These proteins need to follow a very specific sequence of steps to achieve the knotted native conformation; otherwise, they risk falling into a misfolded state.5 It has, been noted that even the simplest proteins, usually twostate folders, can present more subtle topological features that play a role in the folding event and affect folding efficiency
A first batch of 20 cycles of Multiple force-field optimization (MFFO) optimizations was run for all the proteins of Table I, where the criterion for successful folding was that Mean Square Displacement (MSD) < 0.9
In the elastic folder model (EFM), the protein is described as a chain of beads connected by bonds, where the non-bonded interactions are limited to excluded volume and the whole system-specific features are embedded in the angular potentials

Summary

Introduction

Since the discovery of the first knotted native structure in 1994,1 a large number of proteins has been found to entail some degree of topological complexity. According to KnotProt, at present over 1600 proteins are known that feature one of the various kinds of possible topological motifs: these can be knots, slipknots, complex lassos, or links. These proteins need to follow a very specific sequence of steps to achieve the knotted native conformation; otherwise, they risk falling into a misfolded state. It has, been noted that even the simplest proteins, usually twostate folders, can present more subtle topological features that play a role in the folding event and affect folding efficiency. According to KnotProt, at present over 1600 proteins are known that feature one of the various kinds of possible topological motifs: these can be knots, slipknots, complex lassos, or links.2 These proteins need to follow a very specific sequence of steps to achieve the knotted native conformation; otherwise, they risk falling into a misfolded state.. Several descriptors of the native conformation of known proteins were found to be correlated with their folding rate and efficiency.13 Examples of these are the contact order, relative effective contact order, native contact number, the cliquishness (or clustering coefficient), the long range order, the content of local secondary structures, or the native interaction between the polypeptide termini.. Testing on a set of proteins, they observed that their degree of backbone self-entanglement anticorrelates with experimental folding rates.

Methods

Results

Conclusion