The glycoprotein CD93, also known as the complement component C1q receptor (C1qRp), has recently been recognized to play an important role in tumor angiogenesis. It is highly expressed in the endothelial cells of tumor blood vessel and faintly expressed in the non-proliferating endothelium. Multimerin-2 (MMRN2) is a unique endothelial specific extracellular matrix protein that has been implicated in various human tumors. In our previous study, we identified MMRN2 as a specific ligand for CD93 involved in cell adhesion and migration of the activated endothelium. In C-type lectin-like domain (CTLD) region of CD93 extracellular domain, a site-directed mutagenesis identifies different residue hotspots either directly or indirectly involved in the binding. In vitro experiments show that some mutations improve the binding interaction with MMRN2, others reduce it. To explore the effect of mutations on CTLD and to explain the different activity of the mutants, Molecular Dynamic (MD) simulations were performed on wild type of CTLD and the mutated structures, respectively. Moreover, it has been investigated NMA (Normal Mode Analysis) which studies the underlying, large-scale functional motions of a protein. NMA comparative studies of the specific mutations involved in MMRN2-interaction provide useful information for investigating the main structurally and functionally aspects of the protein.Our analysis confirms in vitro results and provides a molecular basis for connecting protein mutations, protein interaction kinetics and network dynamics properties. This study identifies the key interaction surfaces of the CD93-MMRN2 complex and provides a framework for exploring how dynamics features of CD93 binding residues influence CD93-MMRN2 interaction.