CirPred, the first structure modeling and linker design system for circularly permuted proteins

Teng-Ruei Chen,Wei-Cheng Lo,Yu-Wei Huang,Yen-Cheng Lin,Chih-Chieh Chen

doi:10.1186/s12859-021-04403-1

Teng-Ruei Chen, Wei-Cheng Lo + Show 3 more

Open Access

https://doi.org/10.1186/s12859-021-04403-1

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Abstract

BackgroundThis work aims to help develop new protein engineering techniques based on a structural rearrangement phenomenon called circular permutation (CP), equivalent to connecting the native termini of a protein followed by creating new termini at another site. Although CP has been applied in many fields, its implementation is still costly because of inevitable trials and errors.ResultsHere we present CirPred, a structure modeling and termini linker design method for circularly permuted proteins. Compared with state-of-the-art protein structure modeling methods, CirPred is the only one fully capable of both circularly-permuted modeling and traditional co-linear modeling. CirPred performs well when the permutant shares low sequence identity with the native protein and even when the permutant adopts a different conformation from the native protein because of three-dimensional (3D) domain swapping. Linker redesign experiments demonstrated that the linker design algorithm of CirPred achieved subangstrom accuracy.ConclusionsThe CirPred system is capable of (1) predicting the structure of circular permutants, (2) designing termini linkers, (3) performing traditional co-linear protein structure modeling, and (4) identifying the CP-induced occurrence of 3D domain swapping. This method is supposed helpful for broadening the application of CP, and its web server is available at http://10.life.nctu.edu.tw/CirPred/ and http://lo.life.nctu.edu.tw/CirPred/.

Highlights

This work aims to help develop new protein engineering techniques based on a structural rearrangement phenomenon called circular permutation (CP), equivalent to connecting the native termini of a protein followed by creating new ter‐ mini at another site
Comparison of structural models generated by CirPred and conventional modeling methods Since proteins related by CP have different start points of the polypeptide sequence, conventional structure modeling methods typically meet difficulties in finding
When CP occurred at positions close to the center of the polypeptide, the quality of models built by these methods was generally good

Summary

Introduction

This work aims to help develop new protein engineering techniques based on a structural rearrangement phenomenon called circular permutation (CP), equivalent to connecting the native termini of a protein followed by creating new ter‐ mini at another site. To facilitate the utilization of circular permutation (CP) as a protein engineering technique, we carried out this study. Chen et al BMC Bioinformatics (2021) 22:494 usually retain their native structures and functions, sometimes with increased functional diversity or activity [1,2,3]. This property makes CP promising for bioengineering. By artificially creating CPMs, CP has been applied in various fields, such as studying the folding and function of proteins [4, 5], improving the stability, solubility, substrate affinity, substrate specificity, and activity of proteins [6,7,8,9]. It is utilized to create split inteins [13, 14]

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