Table Of ContentFundamentals of
Molecular Structural
Biology
Fundamentals of
Molecular Structural
Biology
Subrata Pal
AcademicPressisanimprintofElsevier
125LondonWall,LondonEC2Y5AS,UnitedKingdom
525BStreet,Suite1650,SanDiego,CA92101,UnitedStates
50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates
TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom
©2020ElsevierInc.Allrightsreserved.
Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicor
mechanical,includingphotocopying,recording,oranyinformationstorageandretrievalsystem,without
permissioninwritingfromthepublisher.Detailsonhowtoseekpermission,furtherinformationabout
thePublisher’spermissionspoliciesandourarrangementswithorganizationssuchastheCopyright
ClearanceCenterandtheCopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/
permissions.
ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher
(otherthanasmaybenotedherein).
Notices
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroaden
ourunderstanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmay
becomenecessary.
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingand
usinganyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformation
ormethodstheyshouldbemindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhom
theyhaveaprofessionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeany
liabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceor
otherwise,orfromanyuseoroperationofanymethods,products,instructions,orideascontainedinthe
materialherein.
LibraryofCongressCataloging-in-PublicationData
AcatalogrecordforthisbookisavailablefromtheLibraryofCongress
BritishLibraryCataloguing-in-PublicationData
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
ISBN:978-0-12-814855-6
ForinformationonallAcademicPresspublicationsvisitour
websiteathttps://www.elsevier.com/books-and-journals
Publisher:AndreGerhardWolff
AcquisitionEditor:MaryPreap
EditorialProjectManager:MeganAshdown
ProductionProjectManager:PunithavathyGovindaradjane
CoverDesigner:MarkRogers
TypesetbySPiGlobal,India
Dedication
To my mother
About the Author
SubrataPal
Bachelor of Science inPhysics,CalcuttaUniversity, Kolkata, India, 1972.
Master ofScience inPhysics,Calcutta University,Kolkata, India, 1974.
Ph.D. inMolecular Biology,Calcutta University,Kolkata, India, 1982.
Asst. Professor,Physics, in aCalcutta University-affiliated college, 1979–82.
VisitingFellow,NationalInstitutesofHealth,NationalCancer Institute,Bethesda,
MD,United States, 1984–87.
Fellow/Claudia Adams Barr Investigator, Harvard Medical School, Dana-Farber
Cancer Institute, Boston,MA, United States, 1988–92.
Assoc. Professor, Molecular Biology, Jadavpur University, Kolkata, India,
1993–2001.
Professor, Molecular Biology, Genomics and Proteomics, Jadavpur University,
Kolkata,India,2001–15.
Claudia Adams Barr special investigator award for basic contribution to cancer
researchat the Dana-Farber Cancer Institute (Harvard Medical School),Boston,
MA,United States, 1991.
xv
Preface
Physicsisgainingaleadingpositioninbiology.Thisisnottobeunderstood
thatphysicsisconqueringbiologyandshovingbiologiststothebackground.
Simply,thescienceweusedtocallbiologyisevolvingintophysics,thereby
confirmingtheviewthatnaturalscienceispassingthroughaperiodof
reconstructiononaunifiedfoundation.
AlexanderKitaigorodsky
Iamaphysicist(1971)
The contribution of physics-based techniques to biology had begun with the
development of the microscope. It marked the beginning of the studies of cell
structure—structuralcellbiology.Subsequently,withthediscoveryofthetwomost
importantmacromoleculesofthelivingcell—DNAandprotein—biologyhadturned
molecular.Inordertounderstandhowthesemoleculesfunction,itbecamenecessary
toelucidate their structures.
Visiblelight-dependentmicroscopyhasitslimitations.Visualizationofmolecu-
larstructuresatatomicresolutionbysuchmicroscopesisnotevenatheoreticalpos-
sibility.Theproblemhasbeenaddressed,inthelastcentury,bythedevelopmentof
three powerful physical methodologies—X-ray crystallography, nuclear magnetic
resonance(NMR),andelectroncrystallography.Withinaspanoflessthantenyears,
thedoublehelicalstructureofDNAandhigh-resolutionstructuresoftwoproteins,
myoglobinandhemoglobin,werepublishedand,withthesediscoveries,theageof
molecular structuralbiology had begun.
Physics has provided not only the techniques and tools for elucidation of the
structure of biomolecules, but also concepts and laws for investigation of their
dynamics. Based on physical laws it is possible to compute biomolecular interac-
tions—as for example, how two molecules would bind, bend, and rotate each
other—leading tomechanistic explanationsfor different biological processes.
Using the techniques mentioned above, more than 150,000 macromolecular
structures have already been solved and deposited in the Worldwide Protein Data
Bank (wwPDB). The number continues to grow at a rapid pace. These structures
have been the basis for molecular biological investigations of various activities
within and involving the cell.
Keeping pace with the scientific developments, institutional biology curricula
havealsobeenevolving.In1965,thefirsteditionofMolecularBiologyoftheGene
was published as “The field of molecular biology was ripe for its first textbook,
defining for the first time the curriculum for undergraduate courses in this topic”
(in Preface to the 7th edition of the book). Presently, there are molecular biology
andrelatedcoursesinuniversitiesacrosstheworld.Thesecourseshavebeenaptly
supported by anumber of popular textbookswritten byrenownedauthors.
xvii
xviii Preface
“Molecular biology” named courses, either introductory or advanced, mostly
centeraroundthe“basicgeneticmechanisms,”namely,maintenanceandexpression
of the genome and their regulation. Such courses are usually catered at the under-
graduatelevelwithdueemphasisonbiologicalandexperimentalaspects.However,
thesubjectistranscendingfromitsdescriptivenaturetoamoremechanisticformat.
Eveninthetraditionalmolecularbiologycourses,explanationandunderstandingof
the basic genetic mechanismsare becomingever moredependent onmacromolec-
ularstructure-functioncorrelation.Thisisprovingtobetruenotonlyforthegraduate
and upper-division courses, butalso for the lower-divisioncourses.
Looking at thegraduate-level courses,we findtitles such asstructuralbiology,
molecularinteractions,molecularsystemsbiology,biophysicalmethods,structural
biochemistry,structureandfunctionofbiologicalmacromolecules,macromolecular
machines, techniques in structural biology, protein folding, molecular recognition
and interactions, structure-function relationship of proteins, structural biology and
proteomics,biophysicalmethodsinlifesciences,etc.Clearlyandexpectedly,these
coursesareinterdisciplinaryinnaturewithajudiciousblendofphysicalandbiolog-
icalsciences.Assuch,itappearsthatnosingletextbookdoesorcancoverallaspects
of the above-named graduate level courses and no individual course can depend
exclusively on one text.
Duringmytrystwithmolecularbiology,firstasastudentandresearcherandsub-
sequentlyasateacher,Ihaveexperiencedhowwonderfullythesubjecthasevolved
inthelastfivedecades.Keepingpacewiththedevelopments,severallandmarktext-
books,writtenbyworld-famousauthors,appearedoneafteranother.Mylearningas
well as my teaching have been enormously benefitted by these textbooks. Yet,
particularlyinmylateryearsofteaching,Ifelttheneedforatextbookgoingdeeper
into the structural aspects of molecular biology, at least as a supplement and not a
substitute tothe already available excellent textbooks.
Itmaybereasonabletoconsiderthatatextbookcontainingthewords“molecu-
lar,” “structural,” and “biology” in its title should embrace macromolecular struc-
tures and interactions with the arms of conventional molecular biology featured
bythe“basic geneticmechanisms.”Suchatextbook wouldbeusefulfortheinter-
disciplinarycoursesaswellastheconventionalmolecularbiologycoursesupgraded
withthe inclusion ofmacromolecular structures.
Withallsuchconsiderationsasoutlinedabove,thepresentbookisanattemptto
catertothefundamentalsofmolecularstructuralbiologyinaconcise,yetcompre-
hensivemanner.Thelayoutofthetexthasbeenstepwise.Thehistoricalperspective
intheIntroductionformsthephilosophicalbasisoftheentirebook,foritismyper-
sonalbeliefthatsciencebereftofphilosophyproducestechniciansandnotscientists.
Chapters1–4providethemathematicalandphysicalconceptsrequiredforthesub-
ject.Theyarelikelytobeusefulinavaryingdegreetothereaderdependingonhis/
her background.Based onthese concepts,Chapters5–7dealwithmacromolecular
structures—formation, determination, and representation. In Chapters 8–13, these
structuresareutilizedtoexplainthebasicgeneticmechanisms.Thechaptersthatfol-
lowdiscusssomeadvancedissuessurroundingmacromolecularstructures,namely,
Preface xix
structuralgenomic/proteomics,cellsignalingandsystemsbiology,macromolecular
assemblies, and computational molecular biology. Covering a wide spectrum, the
bookcanbeusedasareferenceaswellasatextpartiallyfulfillingtherequirements
of the related courses.
Needlesstosay,inscience,everytheoryisprecededbyexperimentsandobser-
vations.Accordingly,anumberofpublishedtextbookshaveelegantlydescribedthe
experiments that have laid the foundation of different concepts and theories in
molecularbiology.Thepresentbook,thoughalludingtotheresultsofmanyofthese
experiments, refrains fromduplicating such efforts.
Instead,inordertodojusticetothetitle,thebookemphasizesthebasicconcepts
andtakescarenottooverburdenthereaderwithexcessiveinformation.Redundancy
isavoidedasmuchaspossible.Forexample,itismentionedinChapter11thatthe
enzyme aminoacyl-tRNA synthetase links an amino acid to a specific tRNA.
Although,basedontheiractivesitearchitectureandconsensussequenceelements,
the familyof aminoacyl-tRNA synthetases is divided into two classes, I andII, all
these enzymes are united by a common aminoacylation reaction that occurs in
twosteps.ThechapterhighlightsonlyoneenzymebelongingtoclassItounderstand
the mechanism of the aminoacylation reaction.
In the same chapter, out of three release factors, bacterial RF1 and RF2 and
eukaryotic eRF1, that are responsible for translation termination, only RF2 is
selectedfordetaileddiscussion.Theunderlyingexpectationisthatifthebasiccon-
cepts are aptly conveyed, the interested reader is competent enough to explore the
literature for mechanisms involving the other factors and identify the subtle
differences.
Itwillbeabsolutelyunwisetoclaimthatthebookisflawless.Criticalcomments
andsuggestionsaremostwelcometoprompttheauthortomakenecessaryamends
and improvements insubsequent editions,if and when opportunityarrives.
Subrata Pal
Acknowledgments
Thebookisdedicatedtothememoryofmymotherwhopassedawaywhiletheman-
uscriptwas in preparation.
Irespectfullyexpressmyindebtednesstomymentors—lateProfessorsBinayak
Dutta-RoyandRamendraKumarPoddar—fromwhomIlearntquantummechanics
andmolecularbiology,respectively.Iwillsorrowfullymissthemwhenthebookis
published.
IgatheredtheinitialconfidenceforundertakingthisdauntingtaskfromProfessor
Geoffrey M. Cooper, author of the widely circulated book The Cell: A Molecular
ApproachandmymentoratDana-FarberCancerInstitute/HarvardMedicalSchool,
Professor Utpal C. Chaudhuri, my teacher in Calcutta University, and Professor
ChanchalDas Gupta,myacademic senior.
MysincerethankstoProfessorAlBurlingameofUniversityofCaliforniainSan
FranciscoandDr.SamuelWilsonofNationalInstituteofEnvironmentalHealthSci-
ences,Durham, North Carolina, for all their encouragement.
My friend and colleague Professor Amitava Das, himself a prolific writer, has
provided plenty of valuable guidance in my endeavor and my Ph.D. student Dr.
SutriptaSarkarhas always been very enthusiastic about the work.
Specialacknowledgments
Mostofthefigures/structuresinthebookhavebeendrawnwithUCSFChimera,developedby
theResourceforBiocomputing,Visualization,andInformaticsattheUniversityofCalifornia,San
Francisco.MydeepgratitudetoProfessorTomE.Ferrin,theDirectorofthefacility,forgivingme
notonlypermission,butalsoencouragementtousetheprogram.
Enormous thanks to Mica H. Haley, Megan Ashdown, and the entire Elsevier
team for their unhesitating help and cooperationin addressing my queries anddif-
ficultiesrightfromthe inception ofthe project tothe publication ofthe book.
And last but not the least, my daughter Sharmishtha and my wife Subhra have
been extremelysupportive ofthis effort inall possibleways.
Subrata Pal
xxi
