Various Ways to Be Negative: Biophysical Characterization of Polyanionic Biomolecules

Negatively charged biopolymers (i.e., polyanions) are ubiquitous across all domains of life and participate in a vast array of cellular processes. Their remarkable diversity raises fundamental questions about how their biophysical properties enable such functional breadth. To investigate these relationships, we performed all-atom molecular dynamics simulations of 11 representative polyanions spanning three major classes of polyanionic biomacromolecules: polynucleotides, polypeptides, and polysaccharides. Each polymer was modeled at a fixed length of 30 repeat units but differed in monomer size, charge per monomer, and linear and radial charge density. We systematically examined how these intrinsic features modulate their biophysical properties and influence solvent organization and conformational preferences in mono- and divalent counterion environments. Our analyses reveal that polyanions differ markedly in compactness and flexibility and that their conformational preferences respond in a system-specific manner to cation identity. While some polymers are strongly modulated by sodium or calcium, others remain comparatively insensitive. Collectively, the polyanions span a broad landscape of conformational space defined by their intrinsic features and the resulting biophysical properties, with each macromolecular family occupying a distinct region of this space. Even within a given family, subtle differences in intrinsic features lead chemically related systems to exhibit unique biophysical properties. These findings show that diverse classes of polyanions possess tunable biophysical properties that evolution could exploit to support specific biological functions, and they further highlight the intriguing question of why biological systems tend to favor polyanions over their positively charged counterparts.