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CONTRIBUTORS
VictoriaEricaJ.Berryman
DepartmentofChemistry,DalhousieUniversity,Halifax,NovaScotia,Canada
TomaszBorowski
JerzyHaberInstituteofCatalysisandSurfaceChemistry,PolishAcademyofSciences,
Krako´w,Poland
RussellJ.Boyd
DepartmentofChemistry,DalhousieUniversity,Halifax,NovaScotia,Canada
EricAndre´ C.Bushnell
DepartmentofChemistry,DalhousieUniversity,Halifax,NovaScotia,andDepartment
ofChemistry,BrandonUniversity,Brandon,Manitoba,Canada
GanglongCui
KeyLaboratoryofTheoreticalandComputationalPhotochemistry,MinistryofEducation,
CollegeofChemistry,BeijingNormalUniversity,Beijing,China
SamP.deVisser
ManchesterInstituteofBiotechnologyandSchoolofChemicalEngineeringand
AnalyticalScience,TheUniversityofManchester,ManchesterM17DN,Manchester,
UnitedKingdom
VictoriaGiselDumas
InstitutodeQu´ımicaF´ısicadelosMaterialesMedioAmbienteyEnerg´ıa(INQUIMAE),
UBA-CONICET,andDepartamentodeQu´ımicaBiolo´gica,FacultaddeCienciasExactasy
Naturales,UniversidaddeBuenosAires,CiudadUniversitaria,BuenosAires,Argentina
Wei-HaiFang
KeyLaboratoryofTheoreticalandComputationalPhotochemistry,MinistryofEducation,
CollegeofChemistry,BeijingNormalUniversity,Beijing,China
JamesW.Gauld
DepartmentofChemistryandBiochemistry,UniversityofWindsor,Windsor,Ontario,
Canada
PaulinoGo´mez-Puertas
MolecularModellingGroup,CenterofMolecularBiology“SeveroOchoa”(CSIC-UAM),
Madrid,Spain
HanselGo´mez
InstitutdeBiotecnologiaideBiomedicina(IBB),andDepartamentdeQu´ımica,Universitat
Auto`nomadeBarcelona,Bellaterra(Barcelona),Spain
LihongLiu
KeyLaboratoryofTheoreticalandComputationalPhotochemistry,MinistryofEducation,
CollegeofChemistry,BeijingNormalUniversity,Beijing,China
ix
x Contributors
Jose´ M.Lluch
InstitutdeBiotecnologiaideBiomedicina(IBB),andDepartamentdeQu´ımica,Universitat
Auto`nomadeBarcelona,Bellaterra(Barcelona),Spain
In˜igoMarcos-Alcalde
MolecularModellingGroup,CenterofMolecularBiology“SeveroOchoa”(CSIC-UAM),
Madrid,Spain
MarceloAdria´nMarti
DepartamentodeQu´ımicaBiolo´gica,FacultaddeCienciasExactasyNaturales,Universidad
deBuenosAires,andInstitutodeQu´ımicaBiolo´gicadelaFacultaddeCienciasExactas
yNaturales(IQUIBICEN)CONICET,CiudadUniversitaria,BuenosAires,Argentina
MarianoMartin
DepartamentodeQu´ımicaBiolo´gica,FacultaddeCienciasExactasyNaturales,Universidad
deBuenosAires,CiudadUniversitaria,BuenosAires,Argentina
LauraMasgrau
InstitutdeBiotecnologiaideBiomedicina(IBB),UniversitatAuto`nomadeBarcelona,
Bellaterra(Barcelona),Spain
Jesu´sI.Mendieta-Moreno
DepartamentodeF´ısicaTeo´ricadelaMateriaCondensadaandCondensedMatterPhysics
Center(IFIMAC),UniversidadAuto´nomadeMadrid,andMolecularModellingGroup,
CenterofMolecularBiology“SeveroOchoa”(CSIC-UAM),Madrid,Spain
Jesu´sMendieta
MolecularModellingGroup,CenterofMolecularBiology“SeveroOchoa”(CSIC-UAM),
andBiomol-InformaticsSL,CampusUAM,Madrid,Spain
FernandaMendoza
InstitutdeBiotecnologiaideBiomedicina(IBB),andDepartamentdeQu´ımica,Universitat
Auto`nomadeBarcelona,Bellaterra(Barcelona),Spain
AnkurOmer
DivisionofToxicology,CSIR-CentralDrugResearchInstitute,Lucknow,UttarPradesh,
andAcademyofScientific&InnovativeResearch(AcSIR),NewDelhi,India
Jose´ Ortega
DepartamentodeF´ısicaTeo´ricadelaMateriaCondensadaandCondensedMatterPhysics
Center(IFIMAC),UniversidadAuto´nomadeMadrid,Madrid,Spain
MatthewQuesne
JerzyHaberInstituteofCatalysisandSurfaceChemistry,PolishAcademyofSciences,
Krako´w,Poland,andManchesterInstituteofBiotechnologyandFacultyofLifeSciences,
TheUniversityofManchester,Manchester,UnitedKingdom
ClaudiaLilia´nRamirez
InstitutodeQu´ımicaF´ısicadelosMaterialesMedioAmbienteyEnerg´ıa(INQUIMAE),
UBA-CONICET,FacultaddeCienciasExactasyNaturales,UniversidaddeBuenosAires,
CiudadUniversitaria,BuenosAires,Argentina
Contributors xi
BenjaminP.Roberts
CentreforeResearch,TheUniversityofAuckland,Auckland,NewZealand
JuanManuelRomero
InstitutodeQu´ımicaF´ısicadelosMaterialesMedioAmbienteyEnerg´ıa(INQUIMAE),
UBA-CONICET,FacultaddeCienciasExactasyNaturales,UniversidaddeBuenosAires,
CiudadUniversitaria,BuenosAires,Argentina
GustavoM.Seabra
DepartamentodeQu´ımicaFundamental,UniversidadeFederaldePernambuco,Cidade
Universita´ria,Recife,Pernambuco,Brazil
ChandraboseSelvaraj
DepartmentofBioinformatics,ComputerAidedDrugDesignandMolecularModelingLab,
ScienceBlock,AlagappaUniversity,Karaikudi,TamilNadu,India
PoonamSingh
DivisionofToxicology,CSIR-CentralDrugResearchInstitute,Lucknow,UttarPradesh,
andAcademyofScientific&InnovativeResearch(AcSIR),NewDelhi,India
SanjeevKumarSingh
DepartmentofBioinformatics,ComputerAidedDrugDesignandMolecularModelingLab,
ScienceBlock,AlagappaUniversity,Karaikudi,TamilNadu,India
VenkatesanSuryanarayanan
DepartmentofBioinformatics,ComputerAidedDrugDesignandMolecularModelingLab,
ScienceBlock,AlagappaUniversity,Karaikudi,TamilNadu,India
MaciejSzaleniec
JerzyHaberInstituteofCatalysisandSurfaceChemistry,PolishAcademyofSciences,
Krako´w,Poland
AmyTimmins
ManchesterInstituteofBiotechnologyandSchoolofChemicalEngineeringandAnalytical
Science,TheUniversityofManchester,ManchesterM17DN,Manchester,United
Kingdom
JuanTorras
DepartmentofChemicalEngineering,EEI,UniversitatPolite`cnicadeCatalunya,Igualada,
Spain
DanielG.Trabada
DepartamentodeF´ısicaTeo´ricadelaMateriaCondensadaandCondensedMatterPhysics
Center(IFIMAC),UniversidadAuto´nomadeMadrid,Madrid,Spain
SamuelB.Trickey
DepartmentsofPhysicsandofChemistry,QuantumTheoryProject,UniversityofFlorida,
Gainesville,Florida,USA
PREFACE
Forbiomolecularsystemsasbigassolvatedproteins,thecombinedquantum
mechanics/molecularmechanics(QM/MM)methodhasproveditsroleasa
potentcomputationaltechnique.Thismethodsynergizestheadvantagesof
both the quantum mechanical (QM) and the molecular mechanical (MM)
methods. The QM method is needed for modeling of electronic processes
including reaction mechanisms and is applicable to systems as big as a few
hundreds of atoms. For biomolecular interactions, however, we need to
be able to model systems as big as several thousands of atoms which are
doable by applying MM methods. The QM/MM method uses the advan-
tagesofboththeQMandtheMMmethods,andhence,itsaccuracyisdueto
theQMmethodandthespeedupisduetotheMMmethod.InaQM/MM
scheme, a QM method is applied to the species of interest for a chemical
transformation and the MM method is used for the treatment of the rest
of the protein and the solvent.
Warshel and Levitt published the first paper on the QM/MM method
and the two authors together with Martin Karplus were awarded the
2013 Nobel Prize in Chemistry (http://www.nobelprize.org/nobel_
prizes/chemistry/laureates/2013/) for the development of this method
for modeling of complex biomolecular systems.
This thematic volume of Advances in Protein Chemistry and Structural
Biology is a collection of some of the most recent advancements in both
QM/MMmethoddevelopmentsandapplicationstobiomolecularsystems.
In Chapter 1 by Juan Torras et al., the development and application of a
new program—PUPIL—for simultaneous treatment of more than one
active site in complex biological systems is reviewed. In Chapter 2 by
Marcelo Marti et al., the application of HyDRA—a hybrid differential
relaxation algorithm—for calculation of an enzymatic reaction free
energyispresented.InChapter3byJose´Ortegaetal.isreviewedtheappli-
cation of a new QM/MM method—FIREBALL/AMBER, synergizing
a density functional theory method—FIREBALL—and the molecular
dynamics package—AMBER—for studying biomolecular interactions.
Chapter 4 by Poonam Singh et al. focuses on QM/MM-based approaches
for the prediction of novel drug–target interactions. Chapter 5 by Sam de
Visser et al. introduces a review of mechanistic computational studies on
metal-containing haloperoxidases and halogenases. Chapter 6 by Russell
xiii
xiv Preface
Boydetal.focusesonexplanationoftheeffectoftheproteinenvironment
and the choice of the quantum mechanics method on the reaction mecha-
nism in QM/MM simulations. Chapter 7 by Maciej Szaleniec et al. repre-
sents on comparative study of metalloenzymes by QM and QM/MM
methods. Important findings of glycosyltransferase reaction mechanisms
modeled by QM/MM methods are reviewed in Chapter 8 by Laura
Masgrau et al. The application of QM/MM methods in modeling of the
excitedstatesofsignificantforthebiologyphotoactiveproteinsisrepresen-
ted in Chapter 9 by Wei-Hai Fang.
I would like to thank all authors of this volume of Advances in Protein
Chemistry and Structural Biology for their excellent contributions to the
volume and for their work. I would like also to thank the APCSB
Editor-in-Chief Dr. Rossen Donev and Helene Kabes, Mary Ann
Zimmerman from Elsevier (Oxford, UK), and Surya Narayanan from
Elsevier (Chennai, India) for their work on this volume.
TATYANA KARABENCHEVA-CHRISTOVA
Northumbria University, Newcastle, United Kingdom
ACKNOWLEDGMENTS
AcknowledgmentsforChapter2,AdvancesinProteinChemistryandStructural
Biology, Volume 98 (Modifications of Natural Peptides for Nanoparticle and
Drug Design, Andrew P. Jallouk, Rohun U. Palekar, Hua Pan, Paul H.
Schlesinger, Samuel A. Wickline).
This work was supported by grants from the National Institutes of
Health (NIH R01 HL073646 and U54 HL112303), the Barnes-Jewish
Hospital Foundation, and the James R. Hornsby Family Dream Garden
Investment Partnership to S.A.W.
xv
CHAPTER ONE
PUPIL: A Software Integration
System for Multi-Scale QM/MM-
MD Simulations and Its
Application to Biomolecular
Systems
Juan Torras*,1, Benjamin P. Roberts†, Gustavo M. Seabra{,
Samuel B. Trickey},1
*DepartmentofChemicalEngineering,EEI,UniversitatPolite`cnicadeCatalunya,Igualada,Spain
†CentreforeResearch,TheUniversityofAuckland,Auckland,NewZealand
{DepartamentodeQu´ımicaFundamental,UniversidadeFederaldePernambuco,CidadeUniversita´ria,Recife,
Pernambuco,Brazil
}DepartmentsofPhysicsandofChemistry,QuantumTheoryProject,UniversityofFlorida,Gainesville,
Florida,USA
1Correspondingauthors:e-mailaddress:[email protected];[email protected]
Contents
1. Introduction 2
2. QM/MM-MDMethodology 7
3. ThePUPILFramework 10
3.1 Features 12
3.2 UserInterface 16
3.3 TechnicalDetails 17
4. BiomolecularApplications 19
5. RecentDevelopments 23
5.1 WorkingwithMultipleActiveZones 24
5.2 TreatmentofLong-RangeElectrostaticInteractions 26
6. Conclusions 27
Acknowledgments 27
References 28
Abstract
PUPIL (Program for User Package Interfacing and Linking) implements a distinctive
multi-scaleapproachtohybridquantummechanical/molecularmechanicalmolecular
dynamics(QM/MM-MD)simulations.Originallydevelopedtointerfacedifferentexternal
programsformulti-scalesimulationwithapplicationsinthematerialssciences,PUPILis
findingincreasinguseinthestudyofcomplexbiologicalsystems.AdvancedMDtech-
niquesfromtheexternalpackagescanbeappliedreadilytoahybridQM/MMtreatment
inwhichtheforcesandenergyfortheQMregioncanbecomputedbyanyoftheQM
AdvancesinProteinChemistryandStructuralBiology,Volume100 #2015ElsevierInc. 1
ISSN1876-1623 Allrightsreserved.
http://dx.doi.org/10.1016/bs.apcsb.2015.06.002
2 JuanTorrasetal.
methodsavailableinanyoftheotherexternalpackages.Here,wegiveasurveyofPUPIL
designphilosophy,mainfeatures,andkeyimplementationdecisions,withanorienta-
tion to biomolecular simulation. We discuss recently implemented features which
enablehighlyrealisticsimulationsofcomplexbiologicalsystemswhichhavemorethan
oneactivesitethatmustbetreatedconcurrently.Examplesaregiven.
1. INTRODUCTION
One of the most remarkable but under-appreciated insights of con-
temporarymolecularandcondensed-phaseresearchisthattheatomiccon-
stituents of molecules behave in many ways according to the classical
mechanicsofNewton.Arelatedbutalsoremarkablerecognitionisthatmol-
eculesthemselvesoftenbehaveinanessentiallyclassicalway.Thusonehas,
forasingleexample,theconceptofdocking,whichoperationallyispurely
classical mechanics. The atomic-level insight had been reached by con-
densed matter and materials physicists (Alder & Wainwright, 1959;
Rahman, 1964) over 50 years ago but in the setting of drastically simpler
systemsthanthosefoundinbiology.Theyconvertedtheinsightintoapow-
erful computational tool by recognizing, in essence, that classical statistical
mechanicsforthemicrocanonicalensembleamountsoperationallytosimply
movingmembersofapopulationofinteractingparticlesviaNewton’sSec-
ondLawforasubstantialtimeintervalandaveragingtheresultantenergetics
toyieldthesystemthermodynamics.(Thisassumesergodicity,oneofseveral
subtleties we leave aside for the purpose of broad perspective.)
Theseideaswereanticipated,ofcourse,bymolecularvibrationtheoryand
analysis on the chemistry side and the corresponding “lattice dynamics” or
phonon treatment in the physics of ordered solids. Both start with a “ball
and stick” model of the system, with the “balls” representing atoms andthe
“sticks”representingbonds(and,inascalemodel,bondlengths).Suchmodels
tracetoAugustWilhelmvonHofmann(Meinel,1992).Vibrationalanalyses
thenreplacethestickswithsuitablychosensprings,corrected,ifneedbe,by
low-orderanharmonicities.Commontobothvibrationalanalysesandmolec-
ular dynamics (MD) is the assumption of a potential energy surface or force
field.Giventheexistenceofbond-lengthdata,itisanobvioussteptocalibrate
the forcefieldsoastorecoverthe bond lengths at theenergyminimum.
In a vernacular way, the summary just given comprises molecular
mechanics (MM). MM is the treatment of molecular systems by methods
of classical mechanics. Statics, i.e., rigid systems, may be enough to yield
valuableinsightforthehuge(bythestandardsofmaterialsphysics)molecules
PUPIL:ASoftwareIntegrationSystem 3
of biological importance. Elementary docking again provides an example:
cantworigidstructuresbefittogetherinasnugway?MDaddstheclassical
dynamics to get at the thermodynamics.
Computationalapproachestothedescriptionofchemicalsystemsinfact
fall into two broad categories. The essential differences lie in assumptions
about chemical interactions and bonding. MM is one category. MM
schemes attempt to describe chemical systems via simple mathematical
models for the forces between classical objects. Common aspects of these
models(theforcefields)include(1)descriptionofbondsthemselves,aswell
as the angles between bonds to the same atom, as simple harmonic oscilla-
tors; (2) inclusion of short-range electrostatic interactions using the
Coulomb inverse-square law directly; (3) inclusion of long-range electro-
static (Coulomb) interactions using a particle-mesh Ewald summation
(Darden, York, & Pedersen, 1993); and (4) description of van der Waals
(dispersion) interactions via one of several Lennard-Jones type potentials.
AllMMapproaches,whetherstaticorMD,areusefulprimarilyforsim-
ulating large chemical systems containing 103 to 105 or more particles,
because the computational tasks are relatively simple: calculation of the
forcesandtemporallydiscretizedsolutiontoNewton’sequation.However,
thedescriptionsofchemicalsystemsareoflimitedaccuracy.Allofthechem-
istryisintheforcefield,soitdeterminesthequalityofMMcalculations.For
simpleliquidssuchasAr,anequallysimpleLennard-Jonesformgoesalong
waytowardprovidingrealisticthermodynamicsfromMD.Butforbiomo-
lecularsystems,constructionofreliablepotentialshasproventobeascien-
tificcraftofitsown.See,forexample,theliteratureofAMBER(Caseetal.,
2006) and CHARMM (Brooks et al., 2009). Moreover, the mathematical
modelsusedareradicallysimplified.Atmostthechemicalsystemcomposi-
tionisthatofindivisibleatoms.Inaunited-atomorcoarse-grainedsimula-
tion, composite particles (e.g., rigid molecules) are used.
ApureMMdescriptionofasystemcannotcaptureperturbationsinelec-
tron density reliably and accurately, much less give a uniformly accurate
description of the vitally important chemical processes of bond breaking
and formation, i.e., chemical reactivity. Moreover, a system can only be
describedusinganMMmodelifthedefinitionofthesystemincludesallnec-
essary variables (such as bonds, angles, and so forth) and the chosen force
fieldcontainstheassociatedparameters.Parametersinthiscontextarecoef-
ficients in the force-field equations whose precise values vary depending
upon the particular types of atoms involved in the bond, angle, torsion,
or nonbonding pair of atoms. If any variable is missing, the MM model is
