Studies On Several Typical Protein Systems Related To Human Health With Molecular Simulations

Proteins are important molecular machines with various biological functions,including reaction catalysis,transportation,nutrient storage,muscle contraction,immunization,and various regulations of biological signaling processes,which are tightly related to human health.Microscopically,these physiological functions of proteins are largely determined by the physical characteristics such as their structural and dynamic fea-tures.The damage of the physiological structures and dynamics would result in the loss of the biological functions and the emergence of the various diseases.This kind of structure-function connections enable us to study the health problems with physical ideas and methods.In this dissertation,our studies would be carried out by focusing on several protein systems which are related to the health problems.The structural and functional characteristics of these protein systems are systematically investigated using molecular simulation methods.The results may provide some molecular information to understand the health-related problems.During recent decades,there are many progresses in the studies of proteins,es-pecially on the physical understanding of the globular proteins.The energy landscape theory of protein is established,and has been successfully applied in various studies on proteins,such as the folding mechanisms and sequence-structure relations.Going beyond these progresses,it is found that there are much more complexities related the structure and dynamics of proteins.For example,for some proteins,there are mul-tiple stable conformations.For these proteins,through the conversion between these conformations,the on/off switching of biological functions could be realized.The cor-responding energy landscape could be considered as the combinations of multiple en-ergetic funnels,and could be regarded as the typical extension of the classical globular proteins.Another kind of characteristic structure with wide interests is the aggregates of proteins,which are frequently observed in many normal or pathological processes in life.The amyloid aggregations related to neurodegenerative diseases and type II diabetes are a typical kind of aggregation structures.There are additional structural characteristics which are different from the monomeric globular proteins.The forma-tion and stability of such kind of structures have a close relation with the occurrence,development and treatment of the related diseases.Additionally,it is found during re-cent years that there are a large number of proteins with disordered structures natively.This class of proteins take an essential role in the regulation of various biological func-tions.Under the physiological condition,this class of proteins have no unique stable conformation.This characteristics prohibit the analysis based on the classical energy landscape theory,and propose new challenges to the theory of proteins.To disclose the underlying connections between sequences and structures is one of the active di-rections of the studies on the proteins and their functions.All these systems would be cover in our dissertation.The realization of protein functions is often affected and modulated by many fac-tors.Especially,in certain processes related to human health,the effects of these fac-tors have a key role in understanding the concerned health problems.For example,it is widely recognized that air pollutants(such as carbon-based nano-structures and other oxides)contribute negatively to human health.Through molecular simulation-s,the characteristics of the interaction between carbon-based nano-structures and the proteins are disclosed.The relevant results could bring some new ideas about the pos-sible toxicity and may stimulate new strategies of treatments.Besides,there are many substances together with the carbon-based nano-structures in pollutants,such as sulfur oxides and nitrogen oxides.The effects of these substances on the human health are important to assess the health impacts of air pollution.Yet,there is a lack of knowl-edge about molecular mechanisms of the toxicity of these molecules.This would also be one part of my dissertation.In my dissertation,several typical protein systems(including calmodulin,amy-loid fibril and intrinsically disordered proteins)are studied with computer simulation methods.The structural stability,interactions and dynamic characteristics are analyzed systematically intrinsically disordered proteins(IDPs).(?)The relationship between the composition and thermodynamic properties of intrinsically disordered proteins is outlined.(?)The effect of the sulfur dioxide on the allosteric processes of calmod-ulin is studied.The physical mechanism of how conformational changes are affected by sulfur dioxide are discovered.(?)The effects of sulfur dioxide on the stability of amyloid fibrils are investigated.The enhancement of the secondary nucleation of fib-rils by sulfur dioxide is concluded.(?)The adsorption dynamics of polypeptides near graphene are studied.The results help to understand the diverse effect of graphene on the aggregation of peptides.These studies on the typical systems provide exam-ples to understand the relationship of sequence and structure of intrinsically disordered proteins and the mechanism and regulation of allostery and aggregation,and help to understand the health-related problems.We firstly study the relationships between sequences and structures of IDPs with the ABSINTH implicit solvent model and Monte Carlo methods.In our simulations,the artificial disordered peptides sequence are composed of the glutamic acid,alanine and lysine.The sequences are randomly assigned.The pattern parameter,mean hy-drophobicity,radius of gyration and various kind of contacts are analyzed for a series of sequences.The results show that both the patterning parameter and mean hydrophobic-ity are determinants to affect the conformations of IDPs.With the increasing alanine,the radius of gyration will decrease for all the related peptide sequences.A structure transition from extend to compact could be observed with increasing alanine num-ber.Correspondingly,we calculate the number of contacts between the residues.It is observed that total number of contacts also monotonically increases as the mean hy-drophobicity of the chain increases.This indicates that there is a transition between disordered and compact structures.Quantitatively,the boundary line between com-pact proteins and extended IDPs is obtained using all-atomic models.These studies demonstrate the competition between the hydrophobic and electrostatic interactions,which affects the structural characteristics of proteins.Based on our results,it is con-cluded that the conformations of IDPs could be regulated by the competition between hydrophobic and electrostatic interactions.Around the boundary,the compositional variation may produce large change of the conformational features.This feature may provide a mechanism for disordered peptides to response the chemical modifications in their functional process.The aggregation of misfolded proteins will cause many misfolding disease.A lot of experimental and simulation studies indicate that carbon-based nanoparticles can interfere with amyloid formation.Yet,the underlying interaction between pep-tide and nano-surface is modulated by various thermodynamic and kinetic factors,and whether nano-materials inhibit or promote amyloid formation is still a controversial is-sue.A clear picture on such a process would benefit the understanding on the toxicity of carbon-based nano-materials.We systematically investigate the adsorption and dis-sociation dynamics of the human islet polypeptides(hIAPP)close to the graphene sur-face.Our simulations show that the ? helix monomer rapidly unfolds and is adsorbed to the graphene surface with a stepwise feature.By analyzing the interactions between peptide and graphene,we found that the competition between peptide-graphene inter-actions and the native interactions produces such kind of cooperative behavior.Besides,the adsorption of hIAPP dimers is simulated.It is found that the adsorbed dimer would be more stable than the free dimers.The detailed structural analysis suggest that the residue 126 in the peptide contributes essentially the stability of the adsorbed dimers.The time scales of the adsorption and dissociation of the dimers are quantitatively de-termined and discussed.These results help to establish a comprehensive picture about the interaction between amyloid fibrils and graphene.Besides,the interaction process between sulfur dioxide and amyloid-? fibrils with all-atomic models.With the steered dynamics,the dissociation pathway of a peptide from the fibril is simulated.Using center-of-mass distance between the peptide and the fibril as reaction coordinate,the free energy profile is calculated with umbrella sampling method.We find that the dissociation free energy decreases with larger con-centration of sulfur dioxide.This is further supported with the sophisticated methods considering molecular mechanics with poisson-boltzmann electronics and surface-area hydrophobicity.Combined with the master equation of fibril growth,the variation of dissociation free energy enhances the secondary nucleation process of fibril,and pro-mote the growth of fibril.This explains the mechanism of toxicity of sulfur dioxide.The effect of protein allosteric process for sulfur dioxide is also a important as-pect.In this dissertation,the interaction between sulfur dioxide and calmodulin(CaM)is studied with molecular simulations.The fraction of native contacts and the cross-ing angle of EF-hand for calmodulin are analyzed for various concentrations of sulfur dioxide.It is found that sulfur dioxide can bind to the specific core of proteins and cause the loss of native contacts for calmodulin.This kind of binding of sulfur dioxide disrupts the active sites of CaM domain,thus leads to the loss of the original function of the protein.Our findings indicate that the cytotoxicity of sulfur dioxide to protein arises not only from the destruction of static protein structures,but also from impacts on their dynamic properties.Through these studies,the relationship between sequences and structures of pro-teins are revealed,which helps to understand the physical basis of conformational flex-ibility for IDPs.Besides,the interactions between proteins and external objects are systematically investigated.The mechanisms of their toxicity are described in their molecular behaviors,which may benefit the understanding on the effects of pollutants in health problem.This dissertation is organized as the following:? Chapter I gives a general introduction to the background and significance of our research topics.Then,the Monte Carlo method,molecular dynamics method,and their related software used in our studies are introduced.? Chapter II,the relationship between the composition and structure of IDPs is investigated with simulations.The phase diagram of IDPs are given based on their conformational and energetic properties.This kind of feature helps to understand the feature of disordered peptides.? Chapter III,the effects of carbon-based nanoparticle and sulfur dioxide to the stability of amyloid peptide are investigated.The adsorption and dissociation of the hIAPP dimers close to graphene surface are simulated.The results show that hIAPP polypeptide could quickly adsorb onto the graphene and significantly lose secondary structure based on the driving force from hydrophobic interactions and 7r-7r stacking interactions.The contribution of sulfur dioxide molecules on A?17-42 fibril is also studied.Our results indicate that the dissociation free energy would decrease with the accumulation of sulfur dioxide molecules,which makes the breaking of fibrils easier and enhances the secondary nucleation of fibrils.? Chapter IV,we studied the interaction between sulfur dioxide and calmodulin with molecular dynamics simulations.Our simulations show that sulfur dioxide can make internal hydrophobic core exposed and significantly change the native conforma-tion.This binding of sulfur dioxide would disrupt the active sites,and thus leading to the loss of the original function of the proteins.Our findings indicate that the cytotox-icity of sulfur dioxide to signal peptide or proteins arises not only from the destruction of static protein structures,but also from impacts on their dynamic properties.? Chapter V is a summary of this dissertation,and the prospects of related topics are discussed.