Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

55-POS Board 55 LIGAND BINDING REMODELS PROTEIN SIDE CHAIN CONFORMATIONAL HETEROGENEITY Stephanie Wankowicz 1,3 ; Saulo H de Oliveira 2 ; Daniel W Hogan 1 ; Henry van den Bedem 2 ; James S Fraser 1 ; 1 University of California San Francisco, Bioengineering and Therapeutic Sciences, San Francisco, CA, USA 2 Atomwise, San Francisco, CA, USA 3 University of California San Francisco, Biophysics Graduate Program, San Francisco, CA, USA While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. While macromolecular X-ray diffraction is commonly interpreted with a static structure, it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, we took advantage of the time- and space-averaged electron density of X- ray structures and applied qFit, an automated and parsimonious multiconformer modeling software. Through using multiconformer models, we were able to more accurately measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity oF side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decrease and relative hydrophobicity increases. Across a series of 13 inhibitor bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from NMR studies suggesting that residual side chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.

63