Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors
Xinheng He,
Ning Huang,
Yuran Qiu,
Jian Zhang,
Yaqin Liu,
Xiao-Lan Yin,
Shaoyong Lu
Affiliations
Xinheng He
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Ning Huang
Northern Huashan Hospital, Fudan University, Shanghai 201907, China
Yuran Qiu
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Jian Zhang
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Yaqin Liu
Medicinal Chemistry and Bioinformatics Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Xiao-Lan Yin
Department of Radiotherapy, Changhai Hospital (Hongkou District) Affiliated to Naval Medical University, Shanghai 200081, China
Shaoyong Lu
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design.
