Analytical Approaches to Improve Accuracy in Solving the Protein Topology Problem.

Kamal Al Nasr,Christopher Jones,Ruba Jebril,Feras Yousef

doi:10.3390/molecules23020028

Kamal Al Nasr, Christopher Jones + Show 2 more

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https://doi.org/10.3390/molecules23020028

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Abstract

To take advantage of recent advances in genomics and proteomics it is critical that the three-dimensional physical structure of biological macromolecules be determined. Cryo-Electron Microscopy (cryo-EM) is a promising and improving method for obtaining this data, however resolution is often not sufficient to directly determine the atomic scale structure. Despite this, information for secondary structure locations is detectable. De novo modeling is a computational approach to modeling these macromolecular structures based on cryo-EM derived data. During de novo modeling a mapping between detected secondary structures and the underlying amino acid sequence must be identified. DP-TOSS (Dynamic Programming for determining the Topology Of Secondary Structures) is one tool that attempts to automate the creation of this mapping. By treating the correspondence between the detected structures and the structures predicted from sequence data as a constraint graph problem DP-TOSS achieved good accuracy in its original iteration. In this paper, we propose modifications to the scoring methodology of DP-TOSS to improve its accuracy. Three scoring schemes were applied to DP-TOSS and tested: (i) a skeleton-based scoring function; (ii) a geometry-based analytical function; and (iii) a multi-well potential energy-based function. A test of 25 proteins shows that a combination of these schemes can improve the performance of DP-TOSS to solve the topology determination problem for macromolecule proteins.

Highlights

IntroductionTo study the relationship between the structure and function of large biological molecular systems, such as proteins, protein inhibitor complexes and macromolecular assemblies, it is crucial to have access to accurate three-dimensional (3D) structural information about the molecule under study
To study the relationship between the structure and function of large biological molecular systems, such as proteins, protein inhibitor complexes and macromolecular assemblies, it is crucial to have access to accurate three-dimensional (3D) structural information about the molecule under study.Traditionally, this information has been extracted from the physical item using one of three main biophysical imaging techniques X-ray crystallography, Nuclear Magnetic Resonance (NMR) and, more recently, Cryo-Electron Microscopy
The true location of the helical secondary structure elements (SSEs)-S was generated from the protein database (PDB) file of the protein structure

Summary

Introduction

To study the relationship between the structure and function of large biological molecular systems, such as proteins, protein inhibitor complexes and macromolecular assemblies, it is crucial to have access to accurate three-dimensional (3D) structural information about the molecule under study This information has been extracted from the physical item using one of three main biophysical imaging techniques X-ray crystallography, Nuclear Magnetic Resonance (NMR) and, more recently, Cryo-Electron Microscopy (cryo-EM). X-ray crystallography and NMR have been the dominant experimental techniques used to determine biological macro-molecular structures and have been used to produce the clear majority of such experimentally determined structures Both suffer from a number of inherent limitations in their utility. In the study of relatively small molecules such limitations are troubling, but they become

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