Recently, a highly contagious novel coronavirus (COVID-19 or SARS-CoV-2) has emerged as a global threat in people's health and global economies. Identification of the potential targets and development of a vaccine or antiviral drugs is an urgent demand. The 5’-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability, protein translation, and for viral immune escape. SARSCoV encodes S-adenosyl-L-methionine dependent (SAM) methyltransferase (MTase) enzyme characterized by nsp16 (2’-O-MTase) for generating the capped structure. The present article highlights the binding mechanisms of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, the conformational dynamics and energetic behind the SAM binding to nsp16 in its monomer and dimer form was analyzed by using an extensive molecular dynamics simulation along with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA). Our results show that the presence of nsp10 increases the favorable van der Waal and electrostatic interactions between the SAM and nsp16, thus nsp10 acts as a stimulator for its strong binding. The interaction profile suggests that hydrophobic interactions were predominately identified for protein-protein interactions. Also, the stable hydrogen bond between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) plays a vital role in the nsp16-nsp10 interface. Further, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Therefore, the dimer interface of nsp16/nsp10 could also be a potential target to suppress the 2’-O-MTase activity of SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding of nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.