A Study of Intrinsically Disordered Proteins from Nuclear Pore Complex

Abstract

Nuclear pore complex (NPC) is giant molecular assembly that acts as a highly selective gate. Its central channel is composed of FG repeat-containing nucleoporins (FG nups), which are natively disordered proteins that facilitate the passage of receptor-cargo complexes through the NPC. However, their mechanism to facilitate selective transport is still unknown. We carried out molecular dynamics simulations of single and multiple FG nups to unveil their dynamics and structures. As an important aspect of our studies of intrinsically disordered proteins (IDPs), we made extensive comparisons between two popular water models, TIP3P and TIP4P-Ew, in combination with Amber ff99sb force field to simulate different IDPs. We found that TIP4P-Ew combined with ff99sb gives better reproduction of experimental observations for FG nups. The reason is because of better solvation of water model to charged side chain of amino acid residues. However, we also identified a caveat of current force field by studying the mutated form of FG nups. We found that the shape of IDPs is much closer to a rod-like shape regardless of whether they are extended or collapsed, which could be a signature of IDPs. Then, we explored the interaction of multiple FG nups to show that the arrangement of the FG nups can be different depending on the inter-chain distances. We identified the influence from the types of FG nups and inter-molecular spacing. FG nups showed a strong dependence of inter-molecular interaction strength on molecular spacing. However, inter-molecular interaction for one type is weaker compared to that of another type. While most of the FG nups of the two types are mainly disordered despite inter- and intra- molecular interactions, we observed noticeable beta-sheet formation at certain inter-molecular spacings, indicating a significant role between inter-molecular interaction and secondary structure formation.