The obtained FEL was shown in Fig. be used as an affordable model to investigate changes in the binding process between the mutated RBD and antibodies. Introduction The novel -coronavirus, SARS-CoV-2, whose sequence is similar to SARS-CoV-1 and MERS-CoV, which induced the human respiratory epidemic at the beginning of this century, is the cause of the human respiratory disease (COVID-19) pandemic worldwide.1,2 This virus has infected more than 160 million people and is associated with more than 3 million deaths.3 SARS-CoV-2 is a single-positive-strand RNA virus, whose genome encodes for four main components: spike, envelope, membrane, and nucleocapsid.4,5 The spike protein (S protein) of SARS-CoV-2 which is used by the virus to bind to human angiotensin-converting-enzyme 2 (ACE2), has been researched thoroughly. ACE2 is present in different tissues in the body, including the Sodium succinate lung, heart and liver,6 and is employed by SARS-CoV-2 as a receptor to bind and infect Sodium succinate human cells. The S trimer comprises three copies of S1 and S2 subunits. The S1 subunit contains 4 domains: S1A, S1B, S1C, and S1D, in which the S1B domain is also called the receptor-binding domain (RBD), which mediates the attachment of the spike protein to the target cell binding to the ACE2 receptor.7 Once the RBD is in the up conformation, it can recognize and bind to ACE2, which leads to conformational changes of the S2 subunit and enables SARS-CoV-2 to fuse with the cell membrane and to enter host cells.1,7 RBD is the main target of neutralizing antibodies (NAbs) which can be isolated from plasma of COVID-19 patients, immunoglobulin libraries, or immunized laboratory animal models.1 These NAbs can be roughly divided into four main classes, of which class 1s and class 2s RBD epitopes overlap with the ACE2-binding site, suggesting a neutralization mechanism that involves direct competition with ACE2. Class 1 antibodies, which are encoded by the immunoglobulin V-gene (VH3-53) segment with complementarity-determining regions 1 and 2 (CDRH1 and CDRH2) and a short CDRH3, are mostly elicited by SARS-CoV-2 infection. On the other hand, when class 2 antibodies also target site I10, 15 which is also target epitopes of class 1 antibodies, they bind to RBD in both up and down conformations of S protein.1,8 Additionally, class 3 antibodies bind outside ACE2 and recognize both up and down RBD, while class 4 antibodies comprise previously described antibodies that cannot block ACE2 and target only to RBD in up conformation.1 Besides RBD, the N-terminal domain (NTD) of protein S is also a popular target for NAbs and many potent monoclonal antibodies directed against this region show great potential in clinical trials for COVID-19 treatment.8 The majority of these antibodies target a single immunodominant site on NTD, including the N1-loop (NTD N-terminus), N3-loop (supersite b-hairpin), and N5 loop (supersite loop). Subsets of these antibodies and NAbs in class 1 and class 3 form multi-donor classes, with a different set of VH germline restricted mode of spike recognition.8 Due to many reasons, including high transmissibility, the longevity of the pandemic, and encountering with immunocompromised hosts, SARS-CoV-2 undergoes different rounds of mutations, which has altered the structures of the virus, modulated its infectivity, and changed the antigenicity of the surface proteins.9 The variants, including United Kingdom (B1.1.7) and South African (B1.351 or 501Y.V2) variants have associated with increased transmissibility and possibly increased mortality.8 Especially, the SARS-CoV-2 lineage in South Africa, included nine mutations in the spike protein, seems to decrease the efficacy of NAb as well as Covid-19 vaccine efficacy of some vaccines currently being used.10,11 The mutations in B1.351 can be divided into two groups, one concentrates in NTD, including four substitutions and a deletion (L18F, D80A, D215G, 242C244, and R246I), and the other involves three substitutions in RBD (K417N, E484K, and N501Y).12 These changes induce S protein biological and structural alterations. Especially, mutation E484K is very critical, which can reduce the effect of NAb.13 Evaluating antibody resistance of the 501Y.V2 SARS-CoV-2 variant is greatly attractive to scientists.8,10,11,14 Understanding the physical insights into the process probably enhances the vaccine developments, but the knowledge is still limited. Therefore, in this context, atomistic simulations were carried out to reveal the insights at the atomic level of the binding process of NAb to 501Y.V2 SARS-CoV-2 RBD. For the first step, PSEN2 structural changes of the 501Y.V2 and wildtype (WT) SARS-CoV-2 RBD + Sodium succinate NAb complexes were characterized unbiased MD simulations. Thermodynamics and kinetics of the binding process were then revealed biased MD simulations. Moreover, fragment of NAb (fNAb) is often used to study the binding of S protein/RBD to antibody.15,16 In this work we also investigated.