CoNSEnsX⁺ Webserver for the Analysis of Protein Structural Ensembles Reflecting Experimentally Determined Internal Dynamics

Abstract

Ensemble-based models of protein structure and dynamics reflecting experimental parameters are increasingly used to obtain deeper understanding of the role of dynamics in protein function. Such ensembles differ substantially from those routinely deposited in the PDB and, consequently, require specialized validation and analysis methodology. Here we describe our completely rewritten online validation tool, CoNSEnsX, that offers a standardized way to assess the correspondence of such ensembles to experimental NMR parameters. The server provides a novel selection feature allowing a user-selectable set and weights of different parameters to be considered. This also offers an approximation of potential overfitting, namely, whether the number of conformers necessary to reflect experimental parameters can be reduced in the ensemble provided. The CoNSEnsX webserver is available at consensx.itk.ppke.hu . The corresponding Python source code is freely available on GitHub ( github.com/PPKE-Bioinf/consensx.itk.ppke.hu ).

Structural impact of GTP binding on downstream KRAS signaling

“…MD and NMR results were compared using the CoNSEnsX+ server. 37 QM/MM calculations were carried out for KRAS-GTP complexes using Jaguar. 38,39 The B3LYP/LACV3P* method was used in combination with OPLS3-based molecular mechanics.…”

“…The effector lobe is responsible for the recruitment and activation of effector proteins; however, the molecular mechanism of this process remains largely unknown. 8,9 The structure of the sequentially conserved Gdomain is similar for all the RAS proteins and contains four main regions that include the phosphate binding loop (P-loop, residues 10-17), switch I (residues [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], switch II (residues 57-76) and nucleobase binding loops (residues 116-120 and 145-147). [10][11][12] Structural investigations on RAS activation are notoriously difficult.…”

Ligand‐dependent intra‐ and interdomain motions in the PDZ12 tandem regulate binding interfaces in postsynaptic density protein‐95

“…Chemical shifts were then ensemble‐averaged over all models in each ensemble and Pearson’s correlation was computed between the experimental and back‐calculated chemical shifts. Back‐calculated order parameters were computed with the CoNSEnsX + webserver . RMSD values were calculated for backbone atoms N, Cɑ, and C. Both order parameters and backbone RMSD were calculated separately for the two domains, after superimposing the structures on residues 1–91 and 96–186 for the full‐length PDZ1 and PDZ2 domains, respectively.…”

Interdependence of intra- and inter-domain motions in the PSD-95 PDZ12 tandem

“…Chemical shifts were than ensembleaveraged over all models in each ensembles and Pearson's correlation was computed between the experimental and back-calculated chemical shifts. Back-calculated order parameters were computed with the CoNSEnsX+ webserver (Dudola et al, 2017). RMSD values were calculated for backbone atoms N, C and C. Both order parameters and ɑ2 helix backbone RMSD were calculated separately for the two domains, after superimposing the structures on residues 4-88 and 99-186 for PDZ1 and PDZ2 domain, respectively.…”