Characterizing the MSMP-CCR2 Interaction through Molecular Dynamics Simulations and Machine Learning Approaches

Area of Science:

• Molecular biology
• Structural biology
• Computational chemistry
• Oncology

Background:

• MicroSeminoProtein (MSMP) is overexpressed in prostate, ovarian, and breast cancers, particularly in tumors resistant to hormonal and antiangiogenic therapies.
• MSMP expression is upregulated in hypoxic tumor microenvironments, promoting tumor growth.
• MSMP interacts with the C-C chemokine receptor type 2 (CCR2), a G protein-coupled receptor (GPCR) on immune cells, stabilizing its active conformation and promoting tumor progression via MAP kinase signaling.

Purpose of the Study:

• To elucidate the structural basis of the MicroSeminoProtein (MSMP)-C-C chemokine receptor type 2 (CCR2) interaction.
• To understand how this interaction stabilizes the active conformation of CCR2 and facilitates downstream signaling.
• To identify key residues and structural features involved in the MSMP-CCR2-G protein complex formation for potential therapeutic targeting.

Main Methods:

• Utilized molecular modeling, molecular dynamics (MD) simulations, and machine learning (ML) techniques.
• Generated high-resolution models of the MSMP-CCR2-G protein complex using AlphaFold2 and refined them with MD simulations.
• Performed comparative analyses with CCL2-CCR2-G protein and unbound CCR2-G protein complexes, including binding free energy calculations and residue-level energy decomposition.

Main Results:

• Identified key conformational rearrangements in CCR2 upon MSMP binding that stabilize its active state.
• MSMP and CCL2 exhibited similar binding free energy profiles to CCR2, despite distinct binding modes.
• Critical residues at the MSMP-CCR2 interface were identified, providing insights into receptor activation mechanisms. ML models highlighted structural features of stable MSMP-CCR2-G protein complexes.

Conclusions:

• The study provides a detailed structural understanding of the MSMP-CCR2 interaction and its role in stabilizing the active receptor conformation.
• Identified specific residues essential for maintaining the stability of the MSMP-CCR2-G protein complex.
• These findings offer a structural basis for developing targeted therapies aimed at disrupting the MSMP-CCR2 interaction in cancer treatment.