Mucherino, A. | bioRxiv Science

bioRxiv2024

Influence of stereochemistry in a local approach for calculating protein conformations

Protein structure prediction is usually based on the use of local conformational information coupled with long-range distance restraints. Such restraints can be derived from the knowledge of a template structure or the analysis of protein sequence alignment in the framework of models arising from the physics of disordered systems. The accuracy of approaches based on sequence alignment, however, is limited in the case where the number of aligned sequences is small. Here we derive protein conformations using only local conformations knowledge by means of the interval Branch-and-Prune algorithm. The computation efficiency is directly related to the knowledge of stereochemistry (bond angle and{omega} values) along the protein sequence, and in particular to the variations of the torsion angle{omega} . The impact of stereochemistry variations is particularly strong in the case of protein topologies defined from numerous long-range restraints, as in the case of protein of {beta} secondary structures. The systematic enumeration of the conformations improves the efficiency of the calculations. The analysis of DNA codons permits to connect the variations of torsion angle{omega} to the positions of rare DNA codons.

bioinformatics↗

bioRxiv2019

Systematic exploration of protein conformational space using a Distance Geometry approach

The optimisation approaches classically used during the determination of protein structure encounter various diffculties, specially when the size of the conformational space is large. Indeed, in such case, algorithmic convergence criteria are more difficult to set up. Moreover, the size of the search space makes it difficult to achieve a complete exploration. The interval Branch-and-Prune (iBP) approach, based on the reformulating of the Distance Geometry Problem (DGP) provides a theoretical frame for the generation of protein conformations, by systematically sampling the conformational space. When an appropriate subset of inter-atomic distances is known exactly, this worst-case exponential-time algorithm is provably complete and fixed-parameter tractable. These guarantees, however, immediately disappear as distance measurement errors are introduced. Here we propose an improvement of this approach: the threading-augmented interval Branch-and-Prune (TAiBP), where the combinatorial explosion of the original iBP approach arising from its exponential complexity is alleviated by partitioning the input instances into consecutive peptide fragments and by using Self-Organizing Maps (SOMs) to obtain clusters of similar solutions. A validation of the TAiBP approach is presented here on a set of proteins of various sizes and structures. The calculation inputs are: a uniform covalent geometry extracted from force field covalent terms, the backbone dihedral angles with error intervals, and a few long-range distances. For most of the proteins smaller than 50 residues and interval widths of 20{degrees}, the TAiBP approach yielded solutions with RMSD values smaller than 3 [A] with respect to the initial protein conformation. The efficiency of TAiBP approach for proteins larger than 50 residues will require the use of non-uniform covalent geometry, and may have benefits from the recent development of residue-specific force-fields.

bioinformatics↗