Response of Two-State Biopolymers to Macromolecular Crowding

Predicting native structures and folding pathways of biopolymers remains a central challenge, particularly under macromolecular crowding, where conformational free energy landscapes are reshaped by excluded-volume interactions [1]. Biopolymers exhibit two-state and multi-state folding, involving a cooperative transition across either a single free energy barrier or a rugged landscape with metastable intermediates. Within coarse-grained models of biopolymers, we develop a shape-based framework for predicting folding behavior in crowded environments. For a bead-spring model of a chain of segments that mutually repel, but whose ends attract, we perform molecular dynamics simulations, with and without hard-sphere crowders, to compute the gyration tensor and its eigenvalue probability distributions, which characterize the fluctuating size and shape of the polymer. Sampling from these probability distributions of the uncrowded polymer and making trial changes in the gyration tensor eigenvalues, we perform Monte Carlo simulations of a polymer modeled as a soft ellipsoid amidst crowders [2]. We find that transitions between folded states depend sensitively on crowder size and concentration. Our approach may provide insight into folding of biopolymers in biological cells.

[1] A. R. Denton, Int. Rev. Cell Mol. Biol. 307, 27 (2014).

[2] W. J. Davis and A. R. Denton, J. Chem. Phys. 149, 124901 (2018).