Abstract
Protein-protein interactions mediated by phosphotyrosine binding (PTB) domains play a crucial role in various cellular processes. In order to understand the structural basis of substrate recognition by PTB domains, multiple explicit solvent atomistic simulations of 100ns duration have been carried out on 6 PTB-peptide complexes with known binding affinities. MM/PBSA binding energy values calculated from these MD trajectories and residue based statistical pair potential score show good correlation with the experimental dissociation constants. Our analysis also shows that the modeled structures of PTB domains can be used to develop less compute intensive residue level statistical pair potential based approaches for predicting interaction partners of PTB domains.
Highlights
phosphotyrosine binding (PTB) domain (Phosphotyrosine binding domain) containing proteins modulate a wide range of physiological processes including neuronal development, immune responses, tissue homeostasis and cell growth[1,2,3]
Peptide array results have indicated that peptides containing identical NPXY or NPXpY motifs bind with differential specificity to different PTB domains
We have identified seven representative structures of PTB domains, which can be used as structural templates for modeling various PTB-peptide complexes
Summary
PTB domain (Phosphotyrosine binding domain) containing proteins modulate a wide range of physiological processes including neuronal development, immune responses, tissue homeostasis and cell growth[1,2,3]. Available high throughput experimental data on PTB-peptide interactions suggest that, even though NPXY, NPXpY or NXXY motifs are necessary for recognition of substrates by PTB domains, sequences containing identical motifs show differential specificity for different PTB domains This highlights the role of sequences flanking PTB domains and potential limitations of motif based approaches in prediction of substrates of PTB domains. MD simulations on PTB-peptide complexes have helped in identifying the crucial binding pocket residues which play key role in peptide recognition Using these binding pocket residues obtained from analysis of MD trajectories, it is possible to use less compute intensive residue based statistical pair potentials and obtain computational binding energies in good correlation with experimental values. Attempt has been made to investigate whether the static crystal structures of PTB domains can be used directly in combination with knowledge based scoring functions like residue based statistical pair potentials for developing fast and efficient models for scoring PTB-peptide complexes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
