[1P-45*] Enhanced Conformational Sampling of Nanobody CDR H3 Loops by Generalized Replica-Exchange with Solute Tempering
Single domain antibodies, known as nanobodies, are potential substitutes for conventional IgG antibodies. They have similar affinities to antigens as the conventional antibodies but are more heat-resistant. In particular, their small size allows us to exploit computational approaches for structural modeling or design. Here, we apply an enhanced sampling method, generalized replica-exchange with solute tempering (gREST) developed recently by Kamiya and Sugita (JCP, 2018), to sample nanobody CDR H3 loop structures. In the conventional replica-exchange methods, temperatures of only a whole system or molecule are exchanged to boost sampling. In gREST, we can flexibly select the temperature-exchange region as a part of a molecule or a part of the potential energy terms. Here, we define the CDR H3 loop as a temperature-exchange region and investigate which potential energy term is effective for efficient sampling of the loop structures. Using a homology-modeling structure as the initial structure, we performed gREST simulations with different potential terms for several nanobodies. The results suggest that using the dihedral-angle energy terms is the best for efficient sampling while there are some limitations depending on nanobody structures.