Molecular Dynamics Analyses of Prion Protein Structures

389 Pages·2018·119.52 MB·English

by  Jiapu Zhang

Focus on Structural Biology 10
Jiapu Zhang
Molecular
Dynamics
Analyses of Prion
Protein Structures
The Resistance to Prion Diseases Down
Under
Focus on Structural Biology
Volume 10
Serieseditor
RobertKaptein,BijvoetCenterforBiomolecularResearch,UtrechtUniversity,
TheNetherlands
Moreinformationaboutthisseriesathttp://www.springer.com/series/5990
Jiapu Zhang
Molecular Dynamics
Analyses of Prion Protein
Structures
The Resistance to Prion Diseases
Down Under
123
JiapuZhang
FacultyofScienceandTechnology
TheFederationUniversityAustralia
MountHelen,Victoria,Australia
ISSN1571-4853 ISSN1571-4853 (electronic)
FocusonStructuralBiology
ISBN978-981-10-8814-8 ISBN978-981-10-8815-5 (eBook)
https://doi.org/10.1007/978-981-10-8815-5
LibraryofCongressControlNumber:2018943680
©SpringerNatureSingaporePteLtd.2018
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof
thematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,
broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation
storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology
nowknownorhereafterdeveloped.
Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication
doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant
protectivelawsandregulationsandthereforefreeforgeneraluse.
Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthisbook
arebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor
theeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinorforany
errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional
claimsinpublishedmapsandinstitutionalaffiliations.
Printedonacid-freepaper
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
TomybrotherJiaqingZhang
whowasdeprivedofeducationbecause
ofourfamilypovertyandtomydearwife
XiaoYanYuan
Preface
Unlikebacteriaandviruses,whicharebasedonDNAandRNA,prionsareunique
as disease-causing agents since they are misfolded proteins. Prions propagate
by deforming harmless, correctly folded proteins into copies of themselves. The
misfoldingisirreversible.Prionsattackthenervoussystemoftheorganism,causing
anincurable,fataldeteriorationofthebrainandnervoussystemuntildeathoccurs.
Some examples of these diseases are bovine spongiform encephalopathy (BSE)
(or called “mad cow” disease) in cattle, chronic wasting disease (CWD) in deers
andelksinNorthAmerica;Creutzfeldt-Jakobdiseases(CJDs)(includingsporadic
CJD (sCJD), hereditary/familiar CJD (fCJD), iatrogenic CJD (iCJD), variant CJD
(vCJD)), fatal familial insomnia (FFI), Gerstmann-Stra¨ussler-Scheinker syndrome
(GSS), Huntington disease-like 1, kuru, and the recently discovered variably
protease-sensitiveprionopathyinhumans;felinespongiformencephalopathy(FSE);
transmissible mink encephalopathy (TME); ungulate spongiform encephalopathy
(USE) (or called exotic ungulate encephalopathy (EUE)); scrapies in sheep and
goats; etc. Prion diseases are called protein “structural conformational” diseases,
because prion contains no nucleic acids, and it is a misshapen or conformation-
changed protein that acts like an infectious agent. The conformational change is
fromanormalcellularprionprotein(PrPC)toadiseasedinfectiousprion(PrPSc).
PrPC is predominant in α-helices, but PrPSc is rich in β-sheets in the form as
amyloid fibrils (cross-β structures), and now numerous experimental structures of
PrPCs(producedbyX-raycrystallographyandnuclearmagneticresonance(NMR)
spectroscopy,etc.)areavailableintheProteinDataBank(PDBBank),sothatitis
veryamenabletobestudiedbymoleculardynamics(MD)techniques.
This book is on MD studies nearly for every PrPC structure with a PDB entry
in the PDB Bank at different temperatures (mainly at room temperature 300K)
underloworneutralpHenvironmentsfor30ns’MDsimulations.Chapter1ofthis
bookistogivesomebasicknowledgeonMD,statisticalmechanics(SM),quantum
mechanics (QM), and the MD and optimization methods used in this book. Then
thisbookisconsistingoffiveparts(PartsI,II,III,IV,andV)brieflydescribedas
follows.
vii
viii Preface
PartI,noteveryspeciesisaffectedbypriondisease;rabbits,dogs,horses,water
buffalo,pigs,chicken,turtles,andfrogsarelowlysusceptibletopriondiseases.We
will well address all these immunity species at 300, 350, 450K under low pH or
neutralpHenvironments:
• Chapter2Rabbit
2.1 TheWild-TypeNMRStructure(PDBEntry2FJ3)
2.2 TheWild-TypeX-rayStructure(PDBEntry3O79)
2.3 TheI214VMutant(NMRStructurePDBEntry2JOM)
2.4 TheS173NMutant(NMRStructurePDBEntry2JOH,X-rayStructurePDB
Entry4HMM)
2.5 TheS170NMutant(X-rayStructurePDBEntry4HLS)
2.6 TheS170NandS174NMutants(X-rayStructurePDBEntry4HMR)
2.7 TheStructureWithouttheDisulfideBond(SS)(HomologyStructure)
• Chapter3Dog
3.1 TheWild-TypeNMRStructure(PDBEntry1XYK)
3.2 TheD159NMutant(HomologyStructure)
• Chapter4Horse,Buffalo,andPig
4.1 Horse’sWild-TypeNMRStructure(PDBEntry2KU4)
4.2 Buffalo’sHomologyStructure
4.3 Pig’sWild-TypeNMRStructure(PDBEntry1XYQ)
• Chapter5Chicken,Turtle,andFrog
5.1 Chicken’sWild-TypeNMRStructure(PDBEntry1U3M)
5.2 Turtle’sWild-TypeNMRStructure(PDBEntry1U5L)
5.3 Frog’sWild-TypeNMRStructure(PDBEntry1XU0)
We will try to find out reasons why the protein in a resistant species allows it to
retain its folding. To compare with the above resistantspecies, other PrPC models
and doppel models (at 300K in neutral pH environment) are also MD studied in
PartI(Chap.6):
• Chapter6OtherSpecies
6.1 SyrianHamster’sWild-TypeNMRStructure(PDBEntry1B10)
6.2 Bovine
6.2.1 TheWild-TypeNMRStructure(PDBEntry1DWY)
6.2.2 TheN-TerminalPrP(1–30)(PDBEntry1SKH)
6.3 Sheep,Ovine,OvisAries
6.3.1 TheWild-TypeX-rayStructure(PDBEntry1UW3)
6.3.2 The Sheep Q168H Mutant (PDB Entry 1XYU) at 300K in Low or
NeutralpHEnvironments)
6.3.3 TheSheepPrPC(135–155)(PDBEntry1S4T)
Preface ix
6.3.4 The Sheep PrPC(142–166) with Mutation Y155A/R156A (PDB
Entries2RMV/W)
6.3.5 The Ovine Q168R Mutant (PDB Entry 1Y2S) at 300K in Low or
NeutralpHEnvironments)
6.3.6 The Ovine H2H3 Domain (PDB Entry 2KTM) at 300K in Low or
NeutralpHEnvironments)
6.3.7 OvisAries
6.3.7.1 TheWild-TypeNMRStructure(PDBEntry2N53)
6.3.7.2 TheOvisAriesΔ190–197(PDBEntry2MV8)
6.3.7.3 TheOvisAriesΔ193–196(PDBEntry2MV9)
6.3.7.4 TheOvisAriesPrP(145–169)(PDBEntry1M25)
6.4 Cat’sWild-TypeNMRStructure(PDBEntry1XYJ)
6.5 Doppel
6.5.1 TheHumanDoppelProtein(PDBEntry1LG4)
6.5.2 MouseDoppelProteins
6.5.2.1 TheWild-Type(PDBEntry1I17)
6.5.2.2 TheSinglePeptide1–30(PDBEntry1Z65)
6.5.3 TheOvineDoppelSinglePeptide1–30(PDBEntry2M1J)
All the mutants of mouse PrP and human PrP are studied in this book. Part II
◦
studies mouse PrP (NMR structures at 37 and 20 C respectively), all mouse PrP
mutants,andotherPrPspecieswhichownahighlyandclearlyorderedβ2-α2loop
(theloopbetweenβ-strand2andα-helix2ofPrP).Mousemutationsintheβ2-α2
loop and in the C-terminal will bring structures with a highly and clearly ordered
β2-α2loop.Whyistheβ2-α2loopinprionprotein(PrPC)afocusforresearchers
andwhatistherolethatmousePrPmutantsplay?Withthesequestionsinmind,we
willfocusontheβ2-α2loopdoingMDanalysesforthefollowingmodelsat300K
underloworneutralpHenvironments:
• Chapter7Mouse’sWild-TypeNMRStructures
◦
7.1 The37 C(310.2K)Structure(PDBEntry2L39)
◦
7.2 The19.85 C(293K)Structure(PDBEntry1AG2)
◦
7.3 The19.85 C(293K)Structure(PDBEntry1XYX)
• Chapter8Mouse’s11Mutants
8.1 TheV166AMutant(PDBEntry2KFO)
◦
8.2 TheD167SMutantat20 C(PDBEntry2KU5)
8.3 TheD167S-N173KMutant(PDBEntry2KU6)
8.4 TheY169GMutant(PDBEntry2L1D)
8.5 TheY169AMutant(PDBEntry2L40)
8.6 TheS170NMutant(PDBEntry2K5O)
8.7 TheS170N-N174TMutant(PDBEntry1Y16)
x Preface
8.8 TheN174TMutant(PDBEntry1Y15)
8.9 TheF175AMutant(PDBEntry2L1E)
8.10 TheY225A-Y226AMutant(PDBEntry2KFM)
◦
8.11 TheY169A-Y225A-Y226A-20 CMutant(PDBEntry2L1K)
• Chapter9OtherSpecieswithanOrderedβ2-α2Loop
9.1 BankVale(ClethrionomysGlareolus)(PDBEntry2K56)
9.2 TammarWallaby(MacropusEugenii)(PDBEntry2KFL)
9.3 Elk(PDBEntry1XYW)at300,350,450KinLoworNeutralpHEnviron-
ment
9.4 Rabbits
9.4.1 NMR Structure (PDB Entry 2FJ3) at 300, 350, 450K in Low pH or
NeutralpHEnvironment(Sect.2.1)
9.4.2 X-ray Structure (PDB Entry 3O79) at 300, 350, 450K in Low or
NeutralpHEnvironment(Sect.2.2)
9.5 Horse (PDB Entry 2KU4) at 300, 350, 450K in Low or Neutral pH
Environment(Sect.4.1)
9.6 Pig(PDBEntry1XYQ)at300,350,450KinLoworNeutralpHEnviron-
ment(Sect.4.3)
Human mutations cause prion diseases such as CJD, GSS, and FFI (especially
some CJDs and the GSS are mainly caused by mutations). In Part III, firstly, we
willdoMDanalysesforthefollowinghuman16mutantsat300KunderneutralpH
environment:
• Chapter10Human’s16Mutants
∗
10.1 ThePrP226 (PDBEntry5L6R)
10.2 TheR220KMutant(PDBEntries1E1U/W)
10.3 TheE219KMutant(PDBEntry2LFT)
10.4 TheQ212PMutant(PDBEntry2KUN)
10.5 TheV210IMutant(PDBEntries2LEJ/V1)
10.5.1 ThepH5.5Structure(PDBEntry2LEJ)
10.5.2 ThepH7.2Structure(PDBEntry2LV1)
10.6 TheV209MMutant(PDBEntry2M8T)
10.7 TheE200KMutant(PDBEntries1FKC/O7)
10.8 TheF198SMutants
10.8.1 WithM129(PDBEntry3HES)
10.8.2 WithV129(PDBEntry3HER)
10.9 TheD178NMutants
10.9.1 TheD178NMutant(PDBEntry3HEQ)
10.9.2 TheD178N-M129VMutant(PDBEntry3HJX)pH7.0Structure
10.9.3 TheD178N-M129VMutant(PDBEntry2K1D)pH4.6Structure