Three-Dimensional Graph Matching to Identify Secondary Structure Correspondence of Medium-Resolution Cryo-EM Density Maps.

Bahareh Behkamal,Mahmoud Naghibzadeh,Zeinab Amiri Tehranizadeh,Mohammad Reza Saberi,Andrea Pagnani,Kamal Al Nasr

doi:10.3390/biom11121773

Abstract

Cryo-electron microscopy (cryo-EM) is a structural technique that has played a significant role in protein structure determination in recent years. Compared to the traditional methods of X-ray crystallography and NMR spectroscopy, cryo-EM is capable of producing images of much larger protein complexes. However, cryo-EM reconstructions are limited to medium-resolution (~4–10 Å) for some cases. At this resolution range, a cryo-EM density map can hardly be used to directly determine the structure of proteins at atomic level resolutions, or even at their amino acid residue backbones. At such a resolution, only the position and orientation of secondary structure elements (SSEs) such as α-helices and β-sheets are observable. Consequently, finding the mapping of the secondary structures of the modeled structure (SSEs-A) to the cryo-EM map (SSEs-C) is one of the primary concerns in cryo-EM modeling. To address this issue, this study proposes a novel automatic computational method to identify SSEs correspondence in three-dimensional (3D) space. Initially, through a modeling of the target sequence with the aid of extracting highly reliable features from a generated 3D model and map, the SSEs matching problem is formulated as a 3D vector matching problem. Afterward, the 3D vector matching problem is transformed into a 3D graph matching problem. Finally, a similarity-based voting algorithm combined with the principle of least conflict (PLC) concept is developed to obtain the SSEs correspondence. To evaluate the accuracy of the method, a testing set of 25 experimental and simulated maps with a maximum of 65 SSEs is selected. Comparative studies are also conducted to demonstrate the superiority of the proposed method over some state-of-the-art techniques. The results demonstrate that the method is efficient, robust, and works well in the presence of errors in the predicted secondary structures of the cryo-EM images.

Highlights

Proteins are one of the essential parts of all organisms that perform most of the tasks of living species
This study aims to find the the correspondence correspondence between between the the α-helices α-helices and and β-strands β-strands detected on the Cryo-electron microscopy (cryo-EM) map with those extracted on the modeled structure
The native correspondence is obtained from the manual labeling of the secondary structure elements (SSEs) in the density map based on the known atomic structure or a structural homolog

Summary

Introduction

Proteins are one of the essential parts of all organisms that perform most of the tasks of living species. Cryo-electron microscopy (cryo-EM) has emerged as an experimental technique to address most of the scalability concerns of the traditional techniques by being able to image large macromolecular complexes, such as ribosomes and viruses, in their native conformations. This widely used technique does not require crystalizing before data acquisition and it is applicable on a molecule larger than ~100 kDa [3,4]. The precise identification of SSEs correspondence enables us to produce an accurate initial 3D structure of a protein that can be refined further by later steps in the model-building pipeline

Objectives

Methods

Results

Conclusion