Quantifying steric hindrance and topological obstruction to protein structure superposition

Background: In computational structural biology, structure comparison is fundamental for our understanding of proteins. Structure comparison is, e.g., algorithmically the starting point for computational studies of structural evolution and it guides our efforts to predict protein structures from the...

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Bibliographic Details
Main Author: Røgen, P. (Author)
Format: Article
Language:English
Published: BioMed Central Ltd 2021
Subjects:
Online Access:View Fulltext in Publisher
LEADER 03318nam a2200205Ia 4500
001 10.1186-s13015-020-00180-3
008 220427s2021 CNT 000 0 und d
020 |a 17487188 (ISSN) 
245 1 0 |a Quantifying steric hindrance and topological obstruction to protein structure superposition 
260 0 |b BioMed Central Ltd  |c 2021 
856 |z View Fulltext in Publisher  |u https://doi.org/10.1186/s13015-020-00180-3 
520 3 |a Background: In computational structural biology, structure comparison is fundamental for our understanding of proteins. Structure comparison is, e.g., algorithmically the starting point for computational studies of structural evolution and it guides our efforts to predict protein structures from their amino acid sequences. Most methods for structural alignment of protein structures optimize the distances between aligned and superimposed residue pairs, i.e., the distances traveled by the aligned and superimposed residues during linear interpolation. Considering such a linear interpolation, these methods do not differentiate if there is room for the interpolation, if it causes steric clashes, or more severely, if it changes the topology of the compared protein backbone curves. Results: To distinguish such cases, we analyze the linear interpolation between two aligned and superimposed backbones. We quantify the amount of steric clashes and find all self-intersections in a linear backbone interpolation. To determine if the self-intersections alter the protein’s backbone curve significantly or not, we present a path-finding algorithm that checks if there exists a self-avoiding path in a neighborhood of the linear interpolation. A new path is constructed by altering the linear interpolation using a novel interpretation of Reidemeister moves from knot theory working on three-dimensional curves rather than on knot diagrams. Either the algorithm finds a self-avoiding path or it returns a smallest set of essential self-intersections. Each of these indicates a significant difference between the folds of the aligned protein structures. As expected, we find at least one essential self-intersection separating most unknotted structures from a knotted structure, and we find even larger motions in proteins connected by obstruction free linear interpolations. We also find examples of homologous proteins that are differently threaded, and we find many distinct folds connected by longer but simple deformations. TM-align is one of the most restrictive alignment programs. With standard parameters, it only aligns residues superimposed within 5 Ångström distance. We find 42165 topological obstructions between aligned parts in 142068 TM-alignments. Thus, this restrictive alignment procedure still allows topological dissimilarity of the aligned parts. Conclusions: Based on the data we conclude that our program ProteinAlignmentObstruction provides significant additional information to alignment scores based solely on distances between aligned and superimposed residue pairs. © 2021, The Author(s). 
650 0 4 |a 57K10 
650 0 4 |a Primary 92C40 
650 0 4 |a Protein topology 
650 0 4 |a Secondary 92E10 
650 0 4 |a Self-avoiding morphs 
650 0 4 |a Structural classification of proteins 
700 1 |a Røgen, P.  |e author 
773 |t Algorithms for Molecular Biology