How Does the Proliferating Cell Nuclear Antigen Modulate Binding Specificity to Multiple Partner Proteins?

Proliferating cell nuclear antigen (PCNA) is a member of the family of sliding clamp proteins that serves as a clamp during DNA repair, DNA replication, cell cycle control, and multiple forms of chromatin modification. PCNA functions as a homotrimer and complexes with multiple proteins in order to carry out each of these varied functions. PCNA binds to different partner proteins in the same region of its structure, called the " interdomain connecting loop", but with different affinities. This interdomain connecting loop is an intrinsically disordered region that takes different conformations when binding to different partner proteins. In this work, we performed all-atom molecular dynamics simulations on PCNA trimer unbound to any partner protein, PCNA bound to peptides from different partner proteins, and PCNA bound to the full Fen 1 protein in two different conformations. Using this massive amount of simulation results, we analyzed whether PCNA in its free trimeric form samples conformations that are similar to those when it is bound to different partner proteins. We observed that PCNA samples many of these peptide-bound conformations even when not bound to the peptides and selects specific conformations when binding to partner proteins. We also identified PCNA-peptide interactions formed in the peptide bound simulation that play a crucial role in complex formation. The calculated binding energies correlate well with the measured binding affinities of various peptides to PCNA. Lastly, we studied the internal dynamics of PCNA and propose a mechanism through which PCNA recruits binding partners. This work highlights the functional role of intrinsically disordered regions in multifunctional proteins such as PCNA.