2026-10-06T06:42:08Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34070875 2026-10-05T16:10:37Z category_1 category_4 category_24 category_873 category_734 category_64 category_128 portal_63 item_type_3 month_year_10_2026

How a Highly Acidic SH3 Domain Binds to Its Intrinsically Disordered Partner through the Formation of an Encounter Complex Intermediate Valeria Jaramillo-Martinez (9507767) Ritika Kukreja (22912344) Michaela R. Cohen (25316587) Ally Mujica (25316590) Samuel Barton (12473548) Oluebube C. Onwuzulu (25316593) Jorge Cardoso (10116751) Matthew J. Dominguez (13171020) Isabelle M. Kekwick (25316596) Jaden Ali (25316599) Gemma M. Bell (25316602) Sydney Rice (23807893) Daniela Poaquiza (25316605) Colin McClure (25316608) Frida Anguiano (25316611) Michael P. Latham (301184) K. Aurelia Ball (1323588) Elliott J. Stollar (9375105) Biophysics Biochemistry Evolutionary Biology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Cancer Hematology likely common among intrinsically disordered protein intrinsically disordered partner highly charged domains apo sh3 domain largest stabilizing effect encounter complex intermediate disordered encounter complex range electrostatic interactions including initial formation bound state structure salt enthalpically destabilizes nmr experiments revealed electrostatic interactions bound state little effect bound complex salt destabilizes simulations show primarily affects often bind multiple steps molecular dynamics less clear kinetic properties help reach detailed picture cations substitute bind idps association rate Electrostatic interactions often play a role in determining the thermodynamic and kinetic properties of protein–protein interactions. However, the role of long-range electrostatic interactions in intrinsically disordered protein (IDP) binding is less clear, as they often bind in multiple steps, including initial formation of a disordered encounter complex, followed by rearrangement into the bound state. We varied the salt concentration to probe the role of long-range electrostatic interactions in the binding of the highly charged AbpSH3 domain and the oppositely charged IDP ArkA. Using isothermal titration calorimetry, we observed that salt enthalpically destabilizes the bound complex. Molecular dynamics and NMR experiments revealed that salt has little effect on the bound state structure. However, simulations show that salt destabilizes the encounter complex intermediate, which primarily affects the association rate as measured by NMR. Consistent with these results, salt has the largest stabilizing effect on the apo SH3 domain, as cations substitute for the transient and long-range electrostatic interactions that can form with ArkA in the complex. We revealed a detailed picture of how a highly charged domain uses long-range, fuzzy, electrostatic interactions to help reach the bound state, a mechanism that is likely common among other highly charged domains that bind IDPs. 2026-10-05T00:00:00Z Dataset Dataset 10.1021/acs.jpcb.6c05098.s003 https://figshare.com/articles/dataset/How_a_Highly_Acidic_SH3_Domain_Binds_to_Its_Intrinsically_Disordered_Partner_through_the_Formation_of_an_Encounter_Complex_Intermediate/34070875 CC BY-NC 4.0