How good are comparative models in the understanding of protein dynamics?
The 3D structure of a protein is essential to understand protein dynamics. If experimentally determined structure is unavailable, comparative models could be used to infer dynamics. However, the effectiveness of comparative models, compared to experimental structures, in inferring dynamics is not clear. To address this, we compared dynamics features of ~800 comparative models with their crystal structures using normal mode analysis. Average similarity in magnitude, direction, and correlation of residue motions is >0.8 (where value 1 is identical) indicating that the dynamics of models and crystal structures are highly similar. Accuracy of 3D structure and dynamics is significantly higher for models built on multiple and/or high sequence identity templates (>40%). Three-dimensional (3D) structure and residue fluctuations of models are closer to that of crystal structures than to templates (TM score 0.9 vs 0.7 and square inner product 0.92 vs 0.88). Furthermore, long-range molecular dynamics simulations on comparative models of RNase 1 and Angiogenin showed significant differences in the conformational sampling of conserved active-site residues that characterize differences in their activity levels. Similar analyses on two EGFR kinase variant models highlight the effect of mutations on the functional state-specific αC helix motions and these results corroborate with the previous experimental observations. Thus, our study adds confidence to the use of comparative models in understanding protein dynamics.
['Yazhini|Arangasamy|A|', 'Srinivasan|Narayanaswamy|N|0000-0002-6566-6239']
D000595:Amino Acid Sequence D001665:Binding Sites D018360:Crystallography, X-Ray D066246:ErbB Receptors D006801:Humans D056004:Molecular Dynamics Simulation D009154:Mutation D011485:Protein Binding D000072756:Protein Conformation, alpha-Helical D000072757:Protein Conformation, beta-Strand D054730:Protein Interaction Domains and Motifs D012259:Ribonuclease, Pancreatic D012260:Ribonucleases D040681:Structural Homology, Protein D013816:Thermodynamics
protein dynamics normal mode analysis molecular dynamics simulation RNase 1 Angiogenin EGFR kinase comparative/homology modeling