On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2

Carolina Corrêa Giron; Aatto Laaksonen; Fernando L. Barroso da Silva

A large diversity of models is available for MD and MC molecular simulations. 38, [49] [50] [51] [52] The need to repeat the calculations on several different physical chemical conditions and to obtain free energy of interactions at them drives the options to the so-called cost-effective coarse-grained (CG) models. These CG models offer the possibility to explore the main physical features of a system with a reduced number of parameters and lower computational costs. 27, 42, 43 During the last years, a fast constant-pH (CpH) CG model has been devised to successfully study proteinprotein interactions of several biological systems (including host-pathogens interactions). 27, 42, 43, 53, 54 The possibility to fully consider the pH effects makes this modeling approach more appealing and appropriated to address this problem. 27, 55 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.05.026377 doi: bioRxiv preprint A sketch of the simulations model is given in Figure 4 . The S RBD proteins and the fragments of the mAbs were modeled as rigid bodies (i.e. bond lengths, angles, and dihedral angles are kept fixed) formed by a set of amino acids placed at positions given by their three-dimensional structures as described above. This additional approximation is justified by the prohibitive . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.05.026377 doi: bioRxiv preprint computational costs of constant-pH methods with pH-dependent conformational changes. 52, 56, 57 Moreover, it is known that SARS-CoV-1 S protein does not exhibit large conformational changes upon the binding to ACE2 at least. 58 Each group of atoms that define an amino acid is converted in a single charged Lennard-Jones (LJ) sphere of radius (Ri) and valence zi. This CG process turns a protein atomistic structure as a collection of charged LJ particles representing their amino acids. The centers-of-masses of the beads (mimicking amino acids) are used to place them accordingly to the coordinates given by the three-dimensional structures. The values of Ri for each type of amino acids were taken from ref. 53 . The valences of all ionizable residues are a function of the solution pH. The fast proton titration scheme (FPTS) 40, 41, 52 was employed both to initially assign these valences zi´s for the amino acids and to let them vary during the simulation sampling at a given pH. This method has proved to predict pKa´s with a very good accuracy at low computational costs. 41 The fundamental physical chemical basis of this titration scheme, its numerical implementation, benchmarks, discussions related to its approximations, pros and cons can be found in previous publications. 40, 41, 52, 59 As illustrated in Figure 4 , two proteins are placed in an electroneutral open cylindrical simulation box, and free to translate back and forward along the axis in which their centers are laying, rotate in any direction and titrate. In this example, these two proteins are the modeled three dimensional structure of the SARS-CoV-2 S RBD and the crystallographic structure of the fragment of the mAb 80R. Unless otherwise specified, simulation runs were carried out with a cell of radius (rcyl) and height (lcyl) equals to 150 and 2