Emergent Mixed Crowder Effects on Protein Dimerization

Abstract

Protein-protein association is affected by non-specific interactions with heterogeneous cellular environment. Quantifying the effect of such environment is still a formidable task. Experimental and simulation studies usually probe the effect of homogeneous crowder environment on protein-protein association which provide inadequate insight into the actual effect in vivo. In this study, we employ a coarse-grained approach1 to model the GB1 (side-by-side) dimerization in attractive lysozyme crowders. The effective protein-crowder attractive interaction is modelled with a Lennard-Jones type potential2 providing qualitative agreement with experimental data3 which was not observed in an earlier study with the standard Lennard-Jones potential4. After validating the single crowder effects, the study further explores the effect of binary crowder mixtures of various sizes and interaction potentials at different volume fractions and mixing ratios to systematically investigate the effect of the complex environment on the dimer stabilization or destabilization. In particular, it is found that smaller crowders play a superior role in overall dimer stability in binary crowder environments. Moreover, the dimer formation stability in binary mixture of crowders emerges from a delicate balance between enthalpy and entropy component that cannot be predicted based on the sole consideration of single crowder properties. In summary, the study offers important insights into the protein-crowder configurations responsible for emergent crowding effects that can be employed to interpret experimental observations under cellular conditions.