Clarifying binding difference of ATP and ADP to extracellular signal-regulated kinase 2 by using molecular dynamics...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Extracellular signal-regulated kinase 2 (ERK2) is a crucial signaling molecule implicated in cancer.
• Targeting ERK2 presents a promising strategy for anticancer drug design.
• Understanding the differential binding of ATP and ADP to ERK2 is vital for drug development.

Purpose of the Study:

• To investigate the binding differences between Adenosine Diphosphate (ADP) and Adenosine Triphosphate (ATP) to Extracellular signal-regulated kinase 2 (ERK2).
• To elucidate the molecular interactions and dynamics governing ADP and ATP binding to ERK2.
• To provide theoretical insights for the design of novel anticancer drugs targeting ERK2.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze the binding behavior of ADP and ATP to ERK2.
• Molecular mechanics with the Poisson-Boltzmann (MM/PBSA) method was used to calculate binding free energies.
• Principal component analysis (PCA) and residue-based free energy decomposition were utilized to study conformational changes and interaction contributions.

Main Results:

• ATP demonstrated a stronger binding affinity to ERK2 compared to ADP.
• Binding of both ADP and ATP induced changes in the motion of helices α1 and α2 within ERK2.
• CH-π interactions with residues Ile29, Val37, Ala50, Leu105, and Leu154, along with hydrogen bonds, were identified as key stabilizing forces for both ligands.

Conclusions:

• The CH-π interactions between ATP and specific ERK2 residues are stronger than those with ADP, explaining ATP's higher binding affinity.
• This detailed molecular understanding of ADP/ATP binding to ERK2 provides a theoretical foundation for designing more effective ERK2-targeted anticancer agents.