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Characterizing the Hot Spots Involved in RON-MSPβ Complex Formation Using In Silico Alanine Scanning Mutagenesis and
Omid Zarei1,2,3, Maryam Hamzeh-Mivehroud2,4, Silvia Benvenuti5
1Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract:
Implication of protein-protein interactions (PPIs) in development of many diseases such as cancer makes them attractive for therapeutic intervention and rational drug design. RON (Recepteur d'Origine Nantais) tyrosine kinase receptor has gained considerable attention as promising target in cancer therapy. The activation of RON via its ligand, macrophage stimulation protein (MSP) is the most common mechanism of activation for this receptor. The aim of the current study was to perform in silico alanine scanning mutagenesis and to calculate binding energy for prediction of hot spots in protein-protein interface between RON and MSPβ chain (MSPβ). In this work the residues at the interface of RON-MSPβ complex were mutated to alanine and then molecular dynamics simulation was used to calculate binding free energy. The results revealed that Gln193, Arg220, Glu287, Pro288, Glu289, and His424 residues from RON and Arg521, His528, Ser565, Glu658, and Arg683 from MSPβ may play important roles in protein-protein interaction between RON and MSP. Identification of these RON hot spots is important in designing anti-RON drugs when the aim is to disrupt RON-MSP interaction. In the same way, the acquired information regarding the critical amino acids of MSPβ can be used in the process of rational drug design for developing MSP antagonizing agents, the development of novel MSP mimicking peptides where inhibition of RON activation is required, and the design of experimental site directed mutagenesis studies.
Insights
Identifying key protein residues in the RON-MSP interaction is crucial for cancer drug development. This study used computational methods to pinpoint critical amino acids in both RON and MSPβ, aiding in the design of targeted therapies.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Biology and Cheminformatics
- Cancer Research and Therapeutics
Background:
- Protein-protein interactions (PPIs) are implicated in various diseases, including cancer, making them targets for drug design.
- The RON (Recepteur d'Origine Nantais) tyrosine kinase receptor, activated by macrophage stimulation protein (MSP), is a significant target in cancer therapy.
Purpose of the Study:
- To identify critical "hot spots" at the protein-protein interface between RON and the MSPβ chain using in silico methods.
- To predict residues essential for the RON-MSP interaction to guide rational drug design.
Main Methods:
- In silico alanine scanning mutagenesis was performed on the RON-MSPβ complex.
- Molecular dynamics simulations were employed to calculate binding free energy for mutated residues.
Main Results:
- Specific residues in RON (Gln193, Arg220, Glu287, Pro288, Glu289, His424) and MSPβ (Arg521, His528, Ser565, Glu658, Arg683) were identified as potentially crucial for interaction.
- These identified residues represent key "hot spots" in the RON-MSP protein-protein interface.
Conclusions:
- The identified RON hot spots are vital for designing drugs that disrupt RON-MSP interactions.
- Understanding critical MSPβ residues facilitates the development of MSP antagonizing agents and RON-inhibiting peptides.
