Lost in the Crowd? How Crowding Affects Drug-Protein Binding

Macromolecular crowding, such as in the interior of biological cells, profoundly influences how molecules interact; however, its effects on drug-target binding rates and pathways remain poorly understood.

In a recent publication, researchers from the Molecular and Cellular Modelling (MCM) group have developed a novel multiresolution Brownian dynamics framework to tackle the complexity of crowded environments, combining atomistic and coarse-grained representations to simulate molecular association. “By simulating protein-small molecule complexes in environments with varying macromolecular crowder densities and types, we discovered that crowding exerts competing effects,” says Riccardo Beccaria, one of the first authors of the study.

The presence of other macromolecules can hinder binding by physically obstructing target sites and slowing down overall diffusion. However, the simulations revealed that crowding can also enhance association rates. “Through mechanisms involving molecular channeling and electrostatic caging — which effectively trap interacting molecules in close proximity — the crowded environment can guide molecules toward successful binding,” Beccaria adds.

Furthermore, the study demonstrates that crowding fundamentally alters not just the rate at which molecules associate, but also their binding pathways. “These results highlight the importance of considering the impact of crowded environments on biomolecular and therapeutic interactions,” says HITS group leader Rebecca Wade.

Graphical Abstract: From a Model of a Crowded System to Multiscale Simulations providing Mechanistic Insights

Publication:

Beccaria R, Muniz-Chicharro A, Wade RC.
Multiscale Brownian dynamics simulations reveal effects of macromolecular crowding on protein-ligand association (29 May 2026)
www.pnas.org/doi/10.1073/pnas.2617950123

Scientific Contact:

Prof. Dr. Rebecca Wade
Molecular and Cellular Modeling group
Heidelberg Institute for Theoretical Studies (HITS)
Phone: +49 6221 533 245
rebecca.wade@h-its.org

Riccardo Beccaria
Molecular and Cellular Modeling group
Heidelberg Institute for Theoretical Studies (HITS)
riccardo.beccaria@h-its.org

Media Contact:

Angela Michel
Head of Communications
Heidelberg Institute for Theoretical Studies (HITS)
angela.michel@h-its.org