University of Oulu

Computing free energies of protein-ligand association

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Author: Donnini, Serena1,2
Organizations: 1University of Oulu, Faculty of Science, Department of Biochemistry
2University of Oulu, Biocenter Oulu
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
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Language: English
Published: 2007
Publish Date: 2007-10-09
Thesis type: Doctoral Dissertation
Defence Note: Academic dissertation to be presented, with the assent of the Faculty of Science of the University of Oulu, for public defence in Raahensali (Auditorium L10), Linnanmaa, on October 19th, 2007, at 12 noon
Reviewer: Doctor Pak-Lee Chau
Professor Antti Poso


Spontaneous changes in protein systems, such as the binding of a ligand to an enzyme or receptor, are characterized by a decrease of free energy. Despite the recent developments in computing power and methodology, it remains challenging to accurately estimate free energy changes. Major issues are still concerned with the accuracy of the underlying model to describe the protein system and how well the calculation in fact emulates the behaviour of the system.

This thesis is largely concerned with the quality of current free energy calculation methods as applied to protein-ligand systems. Several methodologies were employed to calculate Gibbs standard free energies of binding for a collection of protein-ligand complexes, for which experimental affinities were available. Calculations were performed using system description with different levels of accuracy and included a continuum approach, which considers the protein and the ligand at the atomic level but includes solvent as a polarizable continuum, and an all-atom approach that relies on molecular dynamics simulations.

In most such applications, the effects of ionic strength are neglected. However, the severity of this approximation, in particular when calculating free energies of charged ligands, is not very clear. The issue of incorporating ionic strength in free energy calculations by means of explicit ions was investigated in greater detail and considerable attention was given to the affinities of charged peptides in the presence of explicit counter-ions. A second common approximation is concerned with the description of ligands that exhibit multiple protonation states. Because most of current methods do not model changes in the acid dissociation constants of titrating groups upon binding, protonation equilibria of such ligands are not taken into account in free energy calculations. The implications of this approximation when predicting affinities were analysed.

Finally, when calculating free energies of binding, a correct description of the interactions between the protein and the ligand is of fundamental importance. However, active sites of enzymes, where strained conformations may hold a functional role, are not always accurately modelled by molecular mechanics force fields. The case of a strained planar proline in the active site of triosephosphate isomerase was investigated using an hybrid quantum mechanics/molecular mechanics method, which implies a higher level of accuracy.

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Series: Acta Universitatis Ouluensis. A, Scientiae rerum naturalium
ISSN-E: 1796-220X
ISBN: 978-951-42-8574-5
ISBN Print: 978-951-42-8573-8
Issue: 493