Beyond uniform screening: electrostatic heterogeneity dictates solution structure of complex macromolecules

TL;DR

This paper demonstrates that electrostatic heterogeneity critically influences the solution structure of complex macromolecules like antibodies, showing that traditional models fail under strong charge heterogeneity and emphasizing the need for improved electrostatic treatment.

Contribution

It introduces a multi-scale modeling approach that explicitly accounts for electrostatic heterogeneity, challenging conventional screening-based models for complex biomolecular solutions.

Findings

Electrostatic heterogeneity significantly affects antibody solution structure.

Traditional implicit charge models fail for strongly heterogeneous charge distributions.

Accurate electrostatic treatment is crucial for predictive modeling of complex soft-matter systems.

Abstract

The complexity of biomolecular interactions necessitates advanced methodologies to accurately capture their behavior in solution. In this work, we focus on monoclonal antibodies and adopt a multi-scale coarse-graining strategy for their modeling, with particular emphasis on the role of electrostatic interactions. Using scattering experiments, theoretical analysis, and large-scale computer simulations, we explicitly compare two selected case studies-markedly different in their charge distributions. Through mutually corroborating lines of evidence, we demonstrate that conventional approaches relying on electrostatic screening and implicit charge representations fail to capture the structural and thermodynamic properties of antibody solutions when strong charge heterogeneity is present, even at a moderate (amino acid) level of coarse-graining. These findings highlight the importance of a correct treatment of electrostatic interactions and ion screening for heterogeneously- and oppositely-charged colloidal and protein systems. Such considerations are essential to move beyond descriptive models towards a truly predictive framework, with direct implications for the formulation of therapeutics and the treatment of other complex soft-matter systems.