Molecular simulations are employed to compute the free energies of pairwise MAbs association using a minimum free energy algorithm. The simulations are able to predict pathways and minimum energy configurations for the MAb-MAb dimerization in agreement with previous experimental measurements. A steric interaction component, electrostatic interactions, and a nonpolar component of the free energy form the energy scoring function. Electrostatic interactions can be calculated by solving the Poisson-Boltzmann equation. Reduction of SASA upon forming the dimer complex describes the nonpolar energy component. An efficient searching algorithm with grid calculations takes into account for the orientational dependence of the protein-protein interactions. In particular, a small number of configurations adopting complementary geometry with very favorable energy provide the main contribution to the minimum free energy pathway. MAb1 presents favorable free energy of association reproducing experimental trends of high viscosity and dimer formation at high concentration. Free energy landscape and a minimum free energy configuration of the dimer are obtained, and the dimer configuration is further optimized using a full MD simulation. It presents a radius of gyration in agreement with neutron spin echo measurements. Instead, MAb2 shows an unfavorable average free energy, so configurations with favorable free energy are not found. Finally, simulations of the dynamics of MAb association provide useful predictions and insights on the behavior of MAbs in solution in order to understand the dimerization process critical for biomedical applications.

Molecular simulations of MAb-MAb association

247th National Meeting (2014)

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