Association of Globular and Intrinsically Disordered Proteins in Particle Based Coarse-grained Models

Abstract

Particle-based coarse-grained models are routinely used to to understand the influence of cellular environment on protein-protein association. Here we employ an interacting particle based reaction-diffusion simulation strategy to obtain the free energy of association of globular and intrinsically disordered proteins (IDPs) under crowded conditions. The globular protein system consists of two B1 domain of protein G (GB1) monomers undergoing association in presence of protein crowder lysozyme. The interaction between GB1 and lysozyme is modelled with a Lennard-Jones potential having varying potential depth to understand the effect of attractive potential strength on the free energy change. In the IDP system, activation domain of the steroid receptor co-activator 3 (ACTR) and nuclear co-activator binding domain of CBP/p300 (NCBD) are considered in presence of polymer crowder polyethylene glycol (PEG), where the IDPs and PEG interact with a harmonic repulsive potential. The change of free energy due to crowding for globular proteins show opposite sign in comparison with experiments [1,2], whereas for IDPs, the results show similar sign although the magnitude is reduced. Based on these results we propose how particle-based models can be improved to study crowding effects on globular proteins and IDPs.