Prediction of Protein-Protein Binding Interactions in Dimeric Coiled Coils by Information Contained in Folding Energy Landscapes.

Panagiota S Georgoulia,Sinisa Bjelic

doi:10.3390/ijms22031368

Abstract

Coiled coils represent the simplest form of a complex formed between two interacting protein partners. Their extensive study has led to the development of various methods aimed towards the investigation and design of complex forming interactions. Despite the progress that has been made to predict the binding affinities for protein complexes, and specifically those tailored towards coiled coils, many challenges still remain. In this work, we explore whether the information contained in dimeric coiled coil folding energy landscapes can be used to predict binding interactions. Using the published SYNZIP dataset, we start from the amino acid sequence, to simultaneously fold and dock approximately 1000 coiled coil dimers. Assessment of the folding energy landscapes showed that a model based on the calculated number of clusters for the lowest energy structures displayed a signal that correlates with the experimentally determined protein interactions. Although the revealed correlation is weak, we show that such correlation exists; however, more work remains to establish whether further improvements can be made to the presented model.

Highlights

Coiled coils are the simplest form of a protein–protein interface with two or more alpha helices supercoiling around each other to form homo- or heterocomplexes of parallel or antiparallel helical bundles [1]
Each model was calculated by starting from the amino acid sequences of the monomers which were folded by fragment insertion and simultaneously docked to give a dimeric coiled coil complex
The results indicate that metric methods which rely on the counting of states may be better descriptors than those that are solely based on the energetic terms when it comes to predicting binding from de novo simulations of protein–protein interactions, which seems to be the case in predicting folding

Summary

Introduction

Coiled coils are the simplest form of a protein–protein interface with two or more alpha helices supercoiling around each other to form homo- or heterocomplexes of parallel or antiparallel helical bundles [1]. The hallmark of regular left-hand twisted coiled coils is the heptad repeat, wherein the first and fourth position in the pattern is occupied by hydrophobic core residues tightly packing into what is widely known as knobs-into-holes interactions [4,5,6,7] The rules governing this ubiquitous coiled coil structural motif have been extensively studied; for example, the identity per se of the interface residues occupying positions a and d seems to determine the oligomeric state, whereas imposition of polar residues at opposing a-positions lead to a parallel coil assembly. The simplicity and extreme stability of the coiled coils, though highly versatile, have rendered them ideal oligomerization tags They are implicated in a variety of diverse functions, mainly as driving assembly in motor proteins, ion channels, and transcription factors, and leading to structure formation in fibrous proteins [1]. They are found in viral glycoproteins facilitating the entry via protein–protein interactions with host cell receptors

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Conclusion