Investigating The Folding Mechanism Of The N-terminal Domain Of Ribosomal Protein L9

Protein folding is an important subject of life science research.With the development of computer technology,molecular dynamics simulation is increasingly used in the study of protein folding.Because of the high flexibility of protein structure,the computational quantity of molecular simulation increases exponentially with the size of protein.In addition,hundreds of studies have shown that the folding of proteins usually follow multiple paths,which are too difficult to sample for conventional molecular dynamics method.To solve this problem,many accelerated sampling algorithms have been proposed.Recently,we developed a new accelerated sampling method,named Mixing REMD,which combines the advantages of the replica exchange molecular dynamics and the adaptively biased molecular dynamics.On the one hand,it samples efficiently in the collective variable space;on the other hand,the sampling data can be directly used to calculate free energy and construct a folding flux network.This sampling method and the related analysis module are integrated into FSATOOL software.As an application,we use this software to study the folding path of NTL9 protein.NTL9 is the N-terminal domain of ribosomal protein L9.This moderately sized protein has a complex topology and abundant secondary structure fragments.Its structure stability and folding process have been studied by many experiments in the past.However,because of the long folding time on the order of milliseconds,the folding path of the protein has not been constructed through all-atom molecular dynamics simulation.In this work,we study the folding of the protein by Mixing REMD.The solvent environment is represented by the generalized Born model.The simulation results are consistent with experimental observations.In the whole simulation time to several microseconds,NTL9 extensively samples in the conformational space.The sampling efficiency is much higher than conventional molecular dynamics method.Markov state model analysis shows that the folding mechanism of NTL9 protein can be explained by the nucleation-condensation model.The residues on the C-terminal helix are involved in the formation of the folding nucleus.After comparing to the first 39 residue fragment of NTL9,we find that the C-terminal helix of NTL9 protein can greatly affect its folding process and thermodynamic stability.