Aspect Of Self-organizational Phenomena In Protein Folding

Proteins are the primary undertakers of life activities.At present,the research on their structures and dynamics is the most challenging and significant subject in the multidisciplinary field of physics,chemistry and biology.As the development of theory and computer,molecular dynamics simulation is widely used to study protein folding process and mechanism.However,there still exist many problems in this approach.The 2016 Nobel Prize in Physics is a manifestation that the application of topology in analyzing self-organizational states of the nano-scale materials can reveal and explain many exotic physics phenomena.Thus,the topological soliton model is of great inspiration to investigate nano-scale protein molecules at the same point of view.According to the local SO(2)symmetries of backbone ?-carbons,a universal free energy can be deduced in this model.Energy minimum is the dark soliton solution to non-linear Schr¨odinger equation and corresponds to a supersecondary structure in proteins.These solitons are the self-organizational units to constitute protein backbones.This thesis applied topological soliton model to study intrinsically disordered proteins(IDPs),as an extension and exploration of this approach.Moreover,to investigate the origin and evolution of soliton in proteins,topological techniques were introduced to scrutinize molecular dynamics simulation trajectories.The main results in the thesis can be summarized as follows:(1)Based on topological soliton model,the conformational thermostability of the human islet amyloid polypeptide(hIAPP)was investigated.The experiment structure was modeled with a three-soliton model and the influence of SDS micelles on hIAPP's conformation was discussed.Subjecting the model to repeated heating and cooling cycles,the unfolding and folding processes of hIAPP were simulated.It turned out that thermal fluctuations even at low temperature can cause the final conformations to locate at different clusters.Six main final clusters are presumed to be the dynamical transient conformations of isolated monomeric hIAPP in solvent,in line with its intrinsically disordered character.By analyzing their hydrophobic side-chains,a relatively stable cluster with anti-parallel helices structure was identified.Due to its structural feature,conformations in such cluster were proposed to have a tendency of nucleation.(2)The phenomena of topological soliton movements in unbound IDPs under the influence of ambient temperature were scrutinized.A heterodimer of amyloid precursor protein intra-cellular domain(AICD)and a nuclear multi-domain adaptor protein Fe65 was inspected as an example.A high-precision two-soliton model describing AICD conformation was constructed,and then non-equilibrium simulations at different temperatures were performed.Moreover,the final conformations were screened with consideration of heavy atoms' space effect.It was found that when temperature increases until the amplitude of thermal fluctuation is high enough to overcome the energy barriers,solitons jump along the backbone lattice and conformation changes.Finally,there existed seven degenerate energy levels corresponding to various patterns of soliton movement.(3)To inquire how self-organizational structure emerges and moves during the folding process,topological tools were introduced to analyze the molecular dynamics simulation result.Firstly,spin variables were constructed to describe the properties of the backbone and side-chain structure.Thus,a protein chain appears to be analogous to a spin chain and topological soliton resembles the concept of Bloch domain wall.The topological property of the loop at the center of soliton can be quantitatively characterized by the folding index.Then,80 ns molecular dynamics simulations under three different force fields were performed on an?-helical subunit of the HIV envelope glycoprotein gp41.It was found that when isolated the helix of the subunit becomes unstable and starts deforming.Two individual Bloch domain walls were identified and then modeled in terms of soliton model.Besides,the concepts which are familiar in lattice systems,such as the Peierls-Nabarro barrier,also appear in the context of protein backbone,and in fact assume a central role in dictating how the folding proceeds.It can be concluded that the folding process is closely related to the formation and interaction of solitons.