Understanding the Functional Roles of Multiple Extracellular Domains in Cell Adhesion Molecules with a Coarse-Grained Model

•One interesting feature of CAMs is that their extracellular regions almost all contain repeating copies of structural domains.•We used computational simulations to understand why such many extracellular domains need to be evolved through natural selection.•We found that when two cells form a contact, they can be linked more easily by molecules that contain more extracellular domains.•Domains can further be organized together, either within one molecule or between two molecules from the same cell to regulate the process of cell adhesion.•Our study demonstrated the functional importance of multiple domains in CAMs.•The binding between subunits in a complex can be synergistically strengthened during assembly.

Intercellular contacts in multicellular organisms are maintained by membrane receptors called cell adhesion molecules (CAMs), which are expressed on cell surfaces. One interesting feature of CAMs is that almost all of their extracellular regions contain repeating copies of structural domains. It is not clear why so many extracellular domains need to be evolved through natural selection. We tackled this problem by computational modeling. A generic model of CAMs was constructed based on the domain organization of neuronal CAM, which is engaged in maintaining neuron–neuron adhesion in central nervous system. By placing these models on a cell–cell interface, we developed a Monte-Carlo simulation algorithm that incorporates both molecular factors including conformational changes of CAMs and cellular factor including fluctuations of plasma membranes to approach the physical process of CAM-mediated adhesion. We found that the presence of multiple domains at the extracellular region of a CAM plays a positive role in regulating its trans-interaction with other CAMs from the opposite side of cell surfaces. The trans-interaction can further be facilitated by the intramolecular contacts between different extracellular domains of a CAM. Finally, if more than one CAM is introduced on each side of cell surfaces, the lateral binding (cis-interactions) between these CAMs will positively correlate with their trans-interactions only within a small energetic range, suggesting that cell adhesion is an elaborately designed process in which both trans- and cis-interactions are fine-tuned collectively by natural selection. In short, this study deepens our general understanding of the molecular mechanisms of cell adhesion.

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