Mutual population-shift driven antibody-peptide binding elucidated by molecular dynamics simulations.

Area of Science:

• Biochemistry
• Pharmacology
• Computational Biology

Background:

• Antibody-based drugs offer an alternative to traditional small chemical compounds.
• The binding mechanisms and conformational effects of therapeutic antibodies on antigens are not fully understood.

Purpose of the Study:

• To investigate the binding mechanism between the antibody solanezumab and the amyloid-beta (Aβ) peptide.
• To understand the conformational changes and stabilization of both antibody and antigen upon binding.

Main Methods:

• Utilized dynamic docking and path sampling simulations.
• Employed all-atom molecular dynamics simulations.
• Estimated binding free energy through simulation data.

Main Results:

• Successfully reproduced experimental structures of the solanezumab-Aβ complex.
• Identified representative binding pathways and accurately estimated binding free energy.
• Demonstrated solanezumab's preference for monomeric Aβ.

Conclusions:

• The binding of solanezumab to Aβ stabilizes both molecules into specific conformations.
• This interaction follows a novel mutual population-shift model, impacting the dynamics of both the antibody and the peptide.
• Provides insights into the molecular basis of antibody-antigen interactions in drug development.