Combining Cryo-EM Density Map and Residue Contact for Protein Secondary Structure Topologies.

Jing He,Maytha Alshammari

doi:10.3390/molecules26227049

Abstract

Although atomic structures have been determined directly from cryo-EM density maps with high resolutions, current structure determination methods for medium resolution (5 to 10 Å) cryo-EM maps are limited by the availability of structure templates. Secondary structure traces are lines detected from a cryo-EM density map for α-helices and β-strands of a protein. A topology of secondary structures defines the mapping between a set of sequence segments and a set of traces of secondary structures in three-dimensional space. In order to enhance accuracy in ranking secondary structure topologies, we explored a method that combines three sources of information: a set of sequence segments in 1D, a set of amino acid contact pairs in 2D, and a set of traces in 3D at the secondary structure level. A test of fourteen cases shows that the accuracy of predicted secondary structures is critical for deriving topologies. The use of significant long-range contact pairs is most effective at enriching the rank of the maximum-match topology for proteins with a large number of secondary structures, if the secondary structure prediction is fairly accurate. It was observed that the enrichment depends on the quality of initial topology candidates in this approach. We provide detailed analysis in various cases to show the potential and challenge when combining three sources of information.

Highlights

Cryo-electron microscopy is a biophysical technique for determination of molecular structures
We propose a method to map amino acid pairs to secondary structure traces, so that the geometric relationship can be combined with predicted contact pairs to enrich the topological predictions for secondary structures
Possible secondary structure topologies are derived from an optimization of agreement between a set of predicted traces from a Cryo-electron microscopy (cryo-EM) map and a list of predicted sequence segments for secondary structures

Summary

Introduction

Cryo-electron microscopy (cryo-EM) is a biophysical technique for determination of molecular structures. The relative positioning of secondary structures in 3D provides critical information to derive the tertiary structure of a protein, since secondary structures are often major components of a tertiary structure Protein secondary structures, such as α-helices and β-sheets, are the most distinguishable characteristics in a medium-resolution cryo-EM density map, even though amino acids are not discernible at such a resolution. It is possible to use a set of lines to represent the orientation and position of major helices and β-strands in the cryo-EM density map of them medium resolution.Various methods have been developed to detect secondary structure elements such as α-helices and β-sheets from cryo-EM density maps [22,23,24,25,26,27,28,29]. Accurate detection of secondary structure is challenging, since the detection may miss or wrongly detect a helix/β-strand

Methods

Results

Conclusion