Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

QM/MM free-energy perturbation and other methods to estimate ligand-binding affinities

Olsson, Martin LU (2018)
Abstract
Experimental drug discovery is very time-consuming, risky and comes at a huge cost, typically several billion USD per drug. Even though decades of experimental drug discovery have provided cures of many diseases, there are still diseases for which there is no effective drug available. If drug development could be performed
by theoretical and computational methods it would be of great advantage to humanity and is likely to accelerate drug discovery. One of the most promising computational methods is free-energy perturbation, which can provide estimates of protein–ligand binding affinities based on a molecular mechanics (MM)
potential. Due to limitations of empirical potential-energy functions used to describe molecular interaction,... (More)
Experimental drug discovery is very time-consuming, risky and comes at a huge cost, typically several billion USD per drug. Even though decades of experimental drug discovery have provided cures of many diseases, there are still diseases for which there is no effective drug available. If drug development could be performed
by theoretical and computational methods it would be of great advantage to humanity and is likely to accelerate drug discovery. One of the most promising computational methods is free-energy perturbation, which can provide estimates of protein–ligand binding affinities based on a molecular mechanics (MM)
potential. Due to limitations of empirical potential-energy functions used to describe molecular interaction, there has been some interest to perform free-energy perturbation instead at the quantum-mechanics (QM)
level of theory. To avoid the cost of performing sampling at the QM/MM level of theory, thermodynamic cycles can be employed. For this purpose, MM→QM free-energy perturbations in method space are required, but early applications have had convergence problems. In this thesis, different approaches to
converge QM/MM free-energy perturbations in method space are developed and compared to other methods to estimate protein–ligand binding affinities. Methods to obtain QM/MM energies by performing MM→QM free-energy perturbations using thermodynamic cycles are compared to direct alchemical free-energy
perturbation with a QM/MM Hamiltonian. Moreover, alternative methods to improve free-energy perturbations at the MM level of theory by charge perturbations are assessed, as well as the use of QM/MM optimised structures. Furthermore, we study also the binding entropy contribution to ligand-binding affinities for the
cancer target galectin-3. QM/MM free-energy perturbation calculations in this thesis have been converged to a precision of 1 kJ/mol. The calculated free energies agree with experimental data to within 4–6 kJ/mol, which allows for a proper ranking of lead candidates. For diastereomeric inhibitors of galectin-3, both qualitative and quantitative agreement between experimental and converged binding entropy contributions to binding affinities have been obtained with a precision of ~5 kJ/mol. (Less)
Abstract (Swedish)
Proteiner är en av människokroppens byggstenar och har en mängd viktiga och
nödvändiga biologiska funktioner genom att delta i kemiska reaktioner och processer.
De flesta proteiner har en bindningsficka som styr proteinets biologiska funktion
genom bindning av andra molekyler. Denna biologiska funktion kan i vissa fall
kopplas till ett sjukdomstillstånd. Organiska molekyler som binder starkt till
bindningsfickan hos ett protein kan hämma eller lindra ett sjukdomstillstånd. I sådana
fall utgör den organiska molekylen ett läkemedel. En kritisk faktor som avgör om en
organisk molekyl är bättre än en annan organisk molekyl på att binda till ett protein
är bindningsaffiniteten mellan proteinet och den organiska... (More)
Proteiner är en av människokroppens byggstenar och har en mängd viktiga och
nödvändiga biologiska funktioner genom att delta i kemiska reaktioner och processer.
De flesta proteiner har en bindningsficka som styr proteinets biologiska funktion
genom bindning av andra molekyler. Denna biologiska funktion kan i vissa fall
kopplas till ett sjukdomstillstånd. Organiska molekyler som binder starkt till
bindningsfickan hos ett protein kan hämma eller lindra ett sjukdomstillstånd. I sådana
fall utgör den organiska molekylen ett läkemedel. En kritisk faktor som avgör om en
organisk molekyl är bättre än en annan organisk molekyl på att binda till ett protein
är bindningsaffiniteten mellan proteinet och den organiska molekylen.
Hittills har den mesta läkemedelsforskningen bedrivits genom experimentella studier
med syntes av nya organiska molekyler för mätning av deras bindningsaffiniteter till
ett protein. Experimentell läkemedelsforskning är mycket tidskrävande, riskfylld och
kostsam, vanligtvis tiotals miljarder kronor per läkemedel. Även om årtionden av
experimentell läkemedelsupptäckt har tillhandahållit botemedel för olika sjukdomar,
finns det fortfarande sjukdomar för vilka det inte finns något effektivt läkemedel. Det
skulle vara till stor fördel för mänskligheten om sådan läkemedelsutveckling kunde
utföras med teoretiska och datoriserade metoder, vilket sannolikt skulle påskynda
upptäckten av nya läkemedel. I två decennier har den förbättrade prestandan för
datorer och framsteg i att ta fram 3D-modeller av proteiner möjliggjort utveckling av
läkemedel med hjälp av teoretiska metoder.

Denna avhandlings första del handlar om hur man med hjälp av kvantmekanik kan
förbättra metoder att beräkna fria energier, något som konventionellt görs genom att
simulera proteiner och läkemedelsmolekyler med klassisk mekanik och empiriska
potentialfunktioner. Denna utveckling är delvis baserad på metoder att kombinera
kvantmekanik och molekylmekanik, som ursprungligen utvecklades av
nobelpristagaren Arieh Warshel.

Avhandlingens andra del handlar om att förbättra konventionella metoder att beräkna
fria energier genom att modellera biomolekyler med molekylmekanik-baserade
kraftfält. Vi har bl.a. utvecklat korrektioner för att beräkna skillnaden i
bindningsstyrka för två läkemedelsmolekyler som skiljer sig i nettoladdning, för
vilket det hittills inte har funnits några lättillgängliga metoder.

Avhandlingens tredje del handlar om hur man kan tillämpa teoretiska metoder för att
förklara hur små strukturella skillnader mellan läkemedelsmolekyler bidrar till
bindningsaffiniteter genom beräkningar av konformationell entropi för
cancerläkemedel.
(Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Brooks, Bernard R., The Laboratory of Computational Biology, National Institutes of Health, Bethesda, MD, USA
organization
alternative title
QM/MM fri-energi perturbering och andra metoder för att uppskatta fria energier för ligand–bindning
publishing date
type
Thesis
publication status
published
subject
keywords
Computer-aided drug design, protein–ligand binding, molecular dynamics, free-energy perturbation, QM/MM, convergence
pages
170 pages
publisher
Lund University, Faculty of Science, Department of Chemistry, Division of Theoretical Chemistry
defense location
Lecture hall A, Center for chemistry and chemical engineering, Naturvetarvägen 14, Lund
defense date
2018-03-23 10:15:00
ISBN
978-91-7422-577-8
language
English
LU publication?
yes
id
750aba6c-e0a0-4709-a114-193a4a9ae560
date added to LUP
2018-02-27 12:39:11
date last changed
2018-11-21 21:38:18
@phdthesis{750aba6c-e0a0-4709-a114-193a4a9ae560,
  abstract     = {{Experimental drug discovery is very time-consuming, risky and comes at a huge cost, typically several billion USD per drug. Even though decades of experimental drug discovery have provided cures of many diseases, there are still diseases for which there is no effective drug available. If drug development could be performed<br/>by theoretical and computational methods it would be of great advantage to humanity and is likely to accelerate drug discovery. One of the most promising computational methods is free-energy perturbation, which can provide estimates of protein–ligand binding affinities based on a molecular mechanics (MM)<br/>potential. Due to limitations of empirical potential-energy functions used to describe molecular interaction, there has been some interest to perform free-energy perturbation instead at the quantum-mechanics (QM)<br/>level of theory. To avoid the cost of performing sampling at the QM/MM level of theory, thermodynamic cycles can be employed. For this purpose, MM→QM free-energy perturbations in method space are required, but early applications have had convergence problems. In this thesis, different approaches to<br/>converge QM/MM free-energy perturbations in method space are developed and compared to other methods to estimate protein–ligand binding affinities. Methods to obtain QM/MM energies by performing MM→QM free-energy perturbations using thermodynamic cycles are compared to direct alchemical free-energy<br/>perturbation with a QM/MM Hamiltonian. Moreover, alternative methods to improve free-energy perturbations at the MM level of theory by charge perturbations are assessed, as well as the use of QM/MM optimised structures. Furthermore, we study also the binding entropy contribution to ligand-binding affinities for the<br/>cancer target galectin-3. QM/MM free-energy perturbation calculations in this thesis have been converged to a precision of 1 kJ/mol. The calculated free energies agree with experimental data to within 4–6 kJ/mol, which allows for a proper ranking of lead candidates. For diastereomeric inhibitors of galectin-3, both qualitative and quantitative agreement between experimental and converged binding entropy contributions to binding affinities have been obtained with a precision of ~5 kJ/mol.}},
  author       = {{Olsson, Martin}},
  isbn         = {{978-91-7422-577-8}},
  keywords     = {{Computer-aided drug design; protein–ligand binding; molecular dynamics; free-energy perturbation; QM/MM; convergence}},
  language     = {{eng}},
  publisher    = {{Lund University, Faculty of Science, Department of Chemistry, Division of Theoretical Chemistry}},
  school       = {{Lund University}},
  title        = {{QM/MM free-energy perturbation and other methods to estimate ligand-binding affinities}},
  url          = {{https://lup.lub.lu.se/search/files/39152396/PhD_thesis_Martin_A_Olsson_w_cover_SPIKFIL.pdf}},
  year         = {{2018}},
}