Energetic and structural basis for the differences in infectivity between the wild-type and mutant spike proteins of SARS-CoV-2 in the Mexican population

Abstract

SARS-CoV-2 is the causative agent of the ongoing viral pandemic of COVID-19. After the emergence of this virus, it became a global public health concern and quickly evolved into a pandemic. Mexico is currently in the third position in the number of deaths due to SARS-CoV-2. To date, there have been several lineages of SARS-CoV-2 worldwide; in the Mexican population, two variants of the spike protein (S-protein) are found, localized at H49Y and D614G, which have been related to increased infectivity with respect to the wild-type S-protein. To understand how these differences impact the structural behavior of the S-protein of SARS-CoV-2, as well as binding with ACE2, we performed MD simulations combined with the molecular mechanics generalized Born/Poisson-Boltzmann surface area (MMGB(PB)SA) approach starting from X-ray crystallography data. Energetic and structural analysis showed that the differences in infectivity can be explained by differences in affinity of the protein-protein interface between the wild-type and mutant S-protein with ACE2. Conformational analysis showed that molecular recognition between the S-protein and ACE2 is linked to a decrease in the conformational flexibility of wild-type and mutant S-protein; however, an increase in the conformational mobility of ACE2 could also contribute to the binding affinity observed using the MMGB(PB)SA method.

Mechanistic Origin of Different Binding Affinities of SARS-CoV and SARS-CoV-2 Spike RBDs to Human ACE2

“…Although the erection of the RBD is a prerequisite for ACE2 binding, the RBD is an independently folded domain and its erection has only a marginal impact on its overall conformation [17]. As a result, the binding affinity of the spike protein to the ACE2 was usually evaluated using the RBD rather than the spike trimer, although previous computational studies showed that certain mutations outside the SARS-CoV-2 spike RBD were capable of influencing an affinity to the ACE2 through altering the spike conformational dynamics [22,23]. Interestingly, multiple earlier experimental and simulation studies have collectively demonstrated that the SARS-CoV-2 RBD (RBD CoV2 ) has a higher ACE2-binding affinity than the SARS-CoV RBD (RBD CoV ) [16,[24][25][26][27][28][29].…”