Coarse-grained Simulation Of Protein Conformational Change And Allostery

The early version of energy landscape theory assumed the native state of protein is unique and has a well-defined three-dimensional structure.However more and more experimental results indicte that the native state of protein should be an ensemble of possible conformations located at the bottom of the energy landscape recently.Pro-tein can go through transition between these possible conformations.This is protein' s functional dynamics and the part at the bottom of energy landscape is called functional landscape,which is related to protein's function.Protein's functional dynamics usually requires protein's conformational change,as a example,after binding a ligand,protein can go through a large scale conformational transition.This large scale conformational change is related to protein's function.Although there is more and more research on this issue in recent years,but until now,there is lots of questions about the mechanism of protein's conformational change.In this dissertation,I present three works focusing on the conformational transition of a small homo-dimer protein S100A2 and a large molecular machine group ? chaperonin separately.S100A12 is a homo-dimer protein,Ca2+ binding can induce a large conforma-tional change of S100A12,resulting in the expose of the hydrophobic core which is the recognition sites for a number of client proteins involved in a variety of cell sig-naling events.Ca2+ and Zn2+ can promote the dimerization and oligermization of S100A12,that would aids S100A12 to bind to its target protein located at the mem-brane.We adopt a newly developed coarse-grained model,which is based multiscale theory to study the dynamics of S100A12 with the help of molecular simulation.We combined the dimerization,conformational change and ligand binding of S100A12 into our model together,so we can study the coupling between these different dynam?ics.Generally speaking,our results indicated that dimerization,conformational change and ligand binding are not independent mutually but coupled together.Conformational change brings multiple pathway of dimerization and make dimerization complicated process;Ligand binding modulates pathway of dimerization,moreover ligand binding induces conformational change.We also observe obvious frustration in S100A12's dy-namics.Prematurely binding of Ca26 will cause frustration,so backtracking of the prematurely bound Ca2+ is required to facilitate the dimerization.In the conforma-tional change process,H3 helices go through partially unfolding which can greatly decease the free energy barrier of conformational change.Moreover we find that there is a coupling of Ca26 and Zn2+,they can promote each other's binding mutually.Group II chaperonin is a large molecular machine composed of several subunits,which can aid unfolded or misfolded proteins to refold to its native state again.Group II chaperonin goes through a large scale conformational change to encapsulate the sub-strate proteins to its inner cavity,isolate substrate proteins from the crowned environ-ment outside.Until now our knowledge about group II chaperonin is limited,especially on the mechanism of its conformational change and the recognition of substrate pro-teins.With the coarse-grained model developed by multiscale method,we studied the group II chaperonin's conformational change and recoginition of substrate proteins.We found that unlike the group I chaperonin,group II chaperonin's conformational transition is neither a concerted nor a sequential process.During the conformational transition,it would form some "partially closed state",which represents adjacent two or three subunits change to closed state but other subunits adopt open state.The sub-units went through two steps transition in the process:apical domain's counter-clock rotation and inward shrink.The former is much faster then the latter one.From the simulations,we identified the binding sites of substrate proteins in group II chaperonin,which is located at the hydrophobic patches of lid domain and apical do-main.Lid domain's binding site plays a major role in the substrate protein's binding.Substrate proteins' recognition is mainly directed by hydrophobic interaction,how-ever electrostatic interaction can aid substrate proteins' binding.Compared to group I chaperonin,the interaction between group II chaperonin and substrate protein is much weaker,and the substrate proteins adopt quite different conformations when binding to different chaperonins.This dissertation brings forth several innovations:· With the help of coarse-grained model developed by multiscale method,we com-bined S100A12's different dynamics:dimerization,conformational change and ligand binding together to study the coupling between these different dynam-ics firstly and revealed that conformational change cause multiple dimerization pathway,ligand binding modulate dimerization pathway.· We uncover the frustration in S100A12's dynamics,prematurely bound Ca2+ ex-hibits backtracking phenomenon.Moreover dimer and monomer show different degree of cracking.· We revealed the mechanism of group ? chaperonin's conformational change,and showed the difference between two type chaperonins.· We identified the binding sites of group ? chaperonin,and predicted that elec-trostatic interaction can aid substrate proteins' binding to group II chaperonin.Moreover we showed the difference between two type chaperonins in substrate proteins' recognition and binding.This dissertation is organized as the following:.Chapter I is a general introduction to the background of our research topics,as well as the methods and techniques we used in our work.· In Chapter ?,we discussed the coupling of S100A12's dimerization,confor-mational change and ligand binding,and frustration in S100A12's functional dynamics.· In Chapter ?,we studied group II chaperonin's conformational change and recognition,binding of substrate proteins,compared with group I chaperonin,we showed some feature of group II chaperonin..Chapter VI is a summary of this dissertation.