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Computational prediction of monosaccharide binding free energies to lectins with linear interaction energy models
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
2012 (English)In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 33, no 29, 2340-2350 p.Article in journal (Refereed) Published
Abstract [en]

The linear interaction energy (LIE) method to compute binding free energies is applied to lectin-monosaccharide complexes. Here, we calculate the binding free energies of monosaccharides to the Ralstonia solanacearum lectin (RSL) and the Pseudomonas aeruginosa lectin-II (PA-IIL). The standard LIE model performs very well for RSL, whereas the PA-IIL system, where ligand binding involves two calcium ions, presents a major challenge. To overcome this, we explore a new variant of the LIE model, where ligandmetal ion interactions are scaled separately. This model also predicts the saccharide binding preference of PA-IIL on mutation of the receptor, which may be useful for protein engineering of lectins.

Place, publisher, year, edition, pages
2012. Vol. 33, no 29, 2340-2350 p.
Keyword [en]
free energy, saccharides, linear interaction energy, molecular dynamics, Ralstonia solanacearum lectin, Pseudomonas aeruginosa lectin-II
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-183531DOI: 10.1002/jcc.23081ISI: 000309190800007OAI: oai:DiVA.org:uu-183531DiVA: diva2:575168
Available from: 2012-12-07 Created: 2012-10-29 Last updated: 2017-12-07Bibliographically approved
In thesis
1. From Structure to Function with Binding Free Energy Calculations for Codon Reading, Riboswitches and Lectins
Open this publication in new window or tab >>From Structure to Function with Binding Free Energy Calculations for Codon Reading, Riboswitches and Lectins
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Molecular association is part of many important processes in living cells. Computational methods for calculating binding free energies allows for a quantitative examination of biomolecular structures and hypotheses drawn from biochemical experiments. Here, binding free energy calculations for tRNAs and release factors binding to mRNA codons on the ribosome, sugars binding to lectins and purine analogs binding to the purine riboswitch are presented.

The relative affinities between cognate and non-cognate tRNAs for different states involved in codon reading on the ribosome were determined. The calculations show that tRNA discrimination varies between different conformations of the 30S subunit, where the existence of both low and high selectivity states provides an efficient common mechanism for initial selection and proofreading. The simulations reveal a desolvation mechanism for the 30S conformational switch with which the accuracy of peptide bond formation can be amplified.

When an mRNA stop codon (UAA, UAG or UGA) is located in the ribosomal A-site release factors bind to the ribosome and the synthesized protein is released. RF1 is specific for UAA and UAG whereas RF2 is specific for UAA and UGA. The free energy calculations and an analysis of the performed simulations show the mechanisms for how RF1 and RF2 are able to read the stop codons with different specificities. Also mitochondrial release factors were investigated. Vertebrate mitochondria have four stop codons, UAA, UAG, AGA and AGG and two release factors mtRF1 and mtRF1a. The calculations show how the specificities of both mtRF1 and mtRF1a agree with RF1 and that none of them are likely to read the non-standard stop codons AGA and AGG.

The linear interaction energy method has also been examined for the RSL and PA-IIL lectins and for the purine riboswitch. The standard parameterization of the method works well for RSL, but fails for PA-IIL and the purine riboswitch due to compositions of the active sites in these systems. The development of new parameterizations to overcome these problems leads to a better understanding of both the method and the binding mechanisms in these systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1072
Keyword
binding free energy, ribosome, codon reading, release factor, mitochondrial translation, purine riboswitch, lectin, molecular dynamics, free energy perturbation
National Category
Structural Biology
Research subject
Biology with specialization in Structural Biology
Identifiers
urn:nbn:se:uu:diva-207140 (URN)978-91-554-8750-8 (ISBN)
Public defence
2013-10-24, C8:301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2013-10-02 Created: 2013-09-09 Last updated: 2014-01-23

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Sund, JohanÅqvist, Johan

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