Investigating the allosteric response of the PICK1 PDZ domain to different ligands with all-atom simulations

Amy O. Stevens, I. Can Kazan, Banu Ozkan, Yi He

Research output: Contribution to journalArticlepeer-review


The PDZ family is comprised of small modular domains that play critical roles in the allosteric modulation of many cellular signaling processes by binding to the C-terminal tail of different proteins. As dominant modular proteins that interact with a diverse set of peptides, it is of particular interest to explore how different binding partners induce different allosteric effects on the same PDZ domain. Because the PICK1 PDZ domain can bind different types of ligands, it is an ideal test case to answer this question and explore the network of interactions that give rise to dynamic allostery. Here, we use all-atom molecular dynamics simulations to explore dynamic allostery in the PICK1 PDZ domain by modeling two PICK1 PDZ systems: PICK1 PDZ-DAT and PICK1 PDZ-GluR2. Our results suggest that ligand binding to the PICK1 PDZ domain induces dynamic allostery at the αA helix that is similar to what has been observed in other PDZ domains. We found that the PICK1 PDZ-ligand distance is directly correlated with both dynamic changes of the αA helix and the distance between the αA helix and βB strand. Furthermore, our work identifies a hydrophobic core between DAT/GluR2 and I35 as a key interaction in inducing such dynamic allostery. Finally, the unique interaction patterns between different binding partners and the PICK1 PDZ domain can induce unique dynamic changes to the PICK1 PDZ domain. We suspect that unique allosteric coupling patterns with different ligands may play a critical role in how PICK1 performs its biological functions in various signaling networks.

Original languageEnglish (US)
Article numbere4474
JournalProtein Science
Issue number12
StatePublished - Dec 2022


  • PDZ
  • all-atom simulation
  • allosteric effect
  • dynamic coupling index
  • dynamic flexibility index
  • ligand

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


Dive into the research topics of 'Investigating the allosteric response of the PICK1 PDZ domain to different ligands with all-atom simulations'. Together they form a unique fingerprint.

Cite this