Structural and energetic basis of interaction between human estrogen-related receptor γ and environmental endocrine disruptors from multiple molecular dynamics simulations and free energy predictions

Environmental endocrine disruptors (EEDs), a class of molecules that are widespread in our environment, may adversely affect the endocrine system. Exploring the interactions between these compounds and their potential targets is important for assessing their role in the organism. Focused on the human estrogen-related receptor γ (hERRγ) with BPA, BPB, HPTE, BPE, BP(2,2)(Et), and BP(2,2)(MeO) complexes, respectively, we groped for the mechanisms of conformational changes and interactions of hERRγ when binding to these six EEDs by combining multiple molecular dynamics (MD) simulations with energy prediction (MM-PBSA and solvated interaction energy (SIE)). Dynamics analysis results revealed these six EEDs have different effects on the internal dynamics of hERRγ, resulting in significant changes in the interaction of key residues around Leu268, Val313, Leu345, and Phe435 with EEDs, and thus affected its binding energy with these EEDs. The energy calculations further demonstrated that van der Waals interactions are critical for these EEDs binding to hERRγ. These results present detailed molecular insight into the interaction features between EEDs and hERRγ and help guide the search for safer alternatives to BPA.