Molecular Dynamics Simulations Study On The Structural Features Of Several Important Proteins

Recently, the development of computer hardware and software give supports tomany subjects. The molecular dynamics (MD) simulations on biological systems haveattracted widespread attentions. With the help of this technique, we can on one handto investigate the processes of transformation of proteins at atomic levels and toobtain clear information during such transformation on the other hand. Theconformations of the proteins are easily to be affected by various external factors,including the binding of certain endogenous substances to the proteins and themutations of certain key residues. The changes of such conditions will affect thestructures of proteins. Some of these conditions have gained promising achievements,but it is still deficient in the detail researchers at the atomic level.There are five parts in this paper. In Chapter I, we made a brief introduction onthe proteins and amino acids, several important proteins, the characters and thecomputational methods for these proteins. In Chapter II, we summarize the theoreticalmethods employed in this paper, including the computational methods of themolecular mechanics and molecular dynamics simulations. In addition, other methodssuch as molecular docking and QM/MM (ONIOM) method are also described in thispart. Then, we carried on the theoretical investigations on the structural changes andproperties of three different kinds of proteins in Chapter III to Chapter V.1．Highlighting a π–π interaction: a protein modelingand molecular dynamicssimulation study onAnophelesgambiae glutathione S-transferase1-2Cytosolic insect theta class glutathione S-transferases(GSTs) have not beenstudied completely andtheir physiological roles are unknown. A detailedunderstandingof Anopheles gambiae GST (Aggst1-2) requires an accuratestructure,which has not yet been determined. A highquality model structure of Aggst1-2wasconstructed usinghomology modeling and the ligand–protein complex wasobtained by the docking method. Molecular dynamics (MD) simulations were carried out to studyconformational changesand to calculate binding free energy. The results ofMDsimulation indicate that Aggst1-2undergoes small conformationalchanges afterligands dock to the protein, which facilitatethe catalytic reaction. An essentialhydrogen bond was found between the sulfur atom of glutathione (GSH) andthehydrogen atom of hydroxyl group in Ser9, which was in goodagreement withexperimental data. A π–π interaction betweenPhe204and CDNB ligand was alsofound. This interaction seems to be important in stabilization of the ligand.Furtherstudy of binding free energy decomposition revealed a van derWaalsinteraction between two ligands that may play a keyrole in nucleophilic additionreaction. This work will be agood starting point for further determination of thebiologicalrole of cytosolic insect theta class GSTs and will aid the designofstructure-based inhibitors.2．Heparin makes differences: a molecular dynamicssimulation study on thehuman βII-tryptasemonomerHuman β-Tryptase, as an enzyme of trypsin-like activity in mast cell, is animportant target for the treatment of inflammatory and allergic related diseases.Heparin has been inferred playing a vital role in the stabilization of tryptase structuresand maintaining in its active form. Up to now, the structure-function relationshipsbetween heparin and βII-tryptase monomer have not been studied at the atomicresolution as the lack of complex structure of tryptase and heparin. To this end, theexact effect of heparin bonding to βII-tryptase monomer structure has beeninvestigated using molecular docking and molecular dynamics (MD) simulation. TheMD simulation results combined with MM-GB/SA calculations showed that heparinstabilized the β-Tryptase structure mainly through salt bridge interaction. Theaveraged noncovalent interaction (aNCI) method was employed for the visualizationof nonbonding interaction. A crucial loop, which is located in the core region ofβII-tryptase monomer structure, has been found. Arg188and Asp189from this loopact as a salt bridge intermediary between4-mer heparin and0GX. The observation ofsalt bridge between Asp189and P1group of0GX confirms the supposed interactionbetween these two groups. These two residues have been proved to be responsible forthe direction of P1group of0GX. Our study revealed that how heparin affected the activity of human βII-tryptase monomer through salt bridge interactions. Theknowledge of heparin binding characteristics and the key residues contributions in thisstudy may enlighten further inhibitor design of this enzyme and may also improve ourunderstanding of inflammatory and allergic related diseases.3．How mutations affect the ligand-receptor interactions: A combined MD andQM/MM calculations on CYP2E1and its two mutantsCytochrome P450(CYP)2E1is a dual function monoxygenase with a crucialrole in the metabolism of6%drugs on the market at present. The enzyme is oftremendous interest for its associated with alcohol consumption, diabetes, obesity andfasting. Despite the abundant experimental mutagenesis data, the molecular origin andthe structural motifs for the enzymatic activities deficiencies have not beenrationalized at the atomic level. In this regard, we have investigated the effects on thestructural and energetic characteristics upon single point mutations in CYP2E1,N219D and S366C. The MD simulation combined with QM/MM (ONIOM) andnoncovalent interaction (NCI) analysis was carried out on CYP2E1and its twomutants. The results highlight the critical role Phe207, which is responsible for bothstructural flexibility and energetic variation, shortening the gap between the theoryand the experimentally observed results of enzymatic activity decrease. Theunderlying molecular mechanism of the enzymatic activity deficiencies for mutantsmay be attributed to the changes of spatial position for Phe207in the two mutants.This work provides particular explanations on how mutations affect ligand-receptorinteractions based on combined MD and QM/MM calculations. Furthermore, themutational effects on the activity of CYP2E1obtained in the present study arebeneficial for both experimental and computational works of CYPs and may allowresearchers to achieve desirable changes in enzymatic activities.