Abstract
Intrinsically Disordered Peptides and Proteins (IDPs) in solution can span a broad range of conformations that often are hard to characterize by both experimental and computational methods. However, obtaining a significant representation of the conformational space is important to understand mechanisms underlying protein functions such as partner recognition. In this work, we investigated the behavior of the Sic1 Kinase-Inhibitor Domain (KID) in solution by Molecular Dynamics (MD) simulations. Our results point out that application of common descriptors of molecular shape such as Solvent Accessible Surface (SAS) area can lead to misleading outcomes. Instead, more appropriate molecular descriptors can be used to define 3D structures. In particular, we exploited Weighted Holistic Invariant Molecular (WHIM) descriptors to get a coarse-grained but accurate definition of the variegated Sic1 KID conformational ensemble. We found that Sic1 is able to form a variable amount of folded structures even in absence of partners. Among them, there were some conformations very close to the structure that Sic1 is supposed to assume in the binding with its physiological complexes. Therefore, our results support the hypothesis that this protein relies on the conformational selection mechanism to recognize the correct molecular partners.
Highlights
Disordered Peptides and Proteins (IDPs) are biomolecules featuring a high degree of structural diversity, which is tightly related to their function [1,2]
In this study we investigated by Molecular Dynamics (MD) simulations the conformational ensemble of Sic1 Kinase-Inhibitor Domain (KID)
In the case of Sic1 KID, the conformational ensembles determined by both force fields sampled different type of conformations that turned out to be separated by metastable partially folded states among which we found conformations close to the bound state
Summary
Disordered Peptides and Proteins (IDPs) are biomolecules featuring a high degree of structural diversity, which is tightly related to their function [1,2]. Two of the proposed advantages of IDPs are adaptability of their shapes to different binding targets and the capability to do a fast binding process due to their long capture radius, which is called the fly-casting mechanism [10]. Despite their highly flexible structure combined with preformed dynamic binding elements, IDPs are usually able to escape unwanted interactions with non-native partners via the so-called functional misfolding [11]. The preformed secondary structure elements are dynamically involved in a set of intramolecular electrostatic and hydrophobic interactions inside a
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
