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Coding to cure: NMR and thermodynamic software applied to congenital heart disease research
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regardless of scientific field computers have become pivotal tools for data analysis and the field of structural biology is not an exception. Here, computers are the main tools used for tasks including structural calculations of proteins, spectral analysis of nuclear magnetic resonance (NMR) spectroscopy data and fitting mathematical models to data. As results reported in papers heavily rely on software and scripts it is of key importance that the employed computational methods are robust and yield reliable results. However, as many scientific fields are niched and possess a small potential user base the task to develop necessary software often falls on researchers themselves. This can cause divergence when comparing data analyzed by different measures or by using subpar methods. Therein lies the importance of development of accurate computational methods that can be employed by the scientific community.

The main theme of this thesis is software development applied to structural biology, with the purpose to aid research in this scientific field by speeding up the process of data analysis as well as to ensure that acquired data is properly analyzed. Among the original results of this thesis are three user-friendly software:

COMPASS - a resonance assignment software for NMR spectroscopy data capable of analyzing chemical shifts and providing the user with suggestions to potential resonance assignments, based on a meticulous database comparison.

CDpal - a curve fitting software used to fit thermal and chemical denaturation data of proteins acquired by circular dichroism (CD) spectroscopy or fluorescence spectroscopy.

PINT - a line shape fitting and downstream analysis software forNMRspectroscopy data, designed with the important purpose to easily and accurately fit peaks in NMR spectra and extract parameters such as relaxation rates, intensities and volumes of peaks.

This thesis also describes a study performed on variants of the life essential regulatory protein calmodulin that have been associated with the congenital life threatening heart disease long QT syndrome (LQTS). The study provided novel insights revealing that all variants are distinct from the wild type in regards to structure and dynamics on a detailed level; the presented results are useful for the interpretation of results from protein interaction studies. The underlying research of this paper makes use of all three developed software, which validates that all developed methods fulfil a scientific purpose and are capable of producing solid results.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. , p. 76
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1882
National Category
Bioinformatics and Systems Biology
Identifiers
URN: urn:nbn:se:liu:diva-142785DOI: 10.3384/diss.diva-142785ISBN: 9789176854495 (print)OAI: oai:DiVA.org:liu-142785DiVA, id: diva2:1154646
Public defence
2017-11-24, Planck, Fysikhuset, Campus Valla, Linköping, 10:00 (English)
Opponent
Supervisors
Available from: 2017-11-03 Created: 2017-11-03 Last updated: 2017-12-01Bibliographically approved
List of papers
1. Fast and Accurate Resonance Assignment of Small-to-Large Proteins by Combining Automated and Manual Approaches
Open this publication in new window or tab >>Fast and Accurate Resonance Assignment of Small-to-Large Proteins by Combining Automated and Manual Approaches
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2015 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 11, no 1, p. e1004022-Article in journal (Refereed) Published
Abstract [en]

The process of resonance assignment is fundamental to most NMR studies of protein structure and dynamics. Unfortunately, the manual assignment of residues is tedious and time-consuming, and can represent a significant bottleneck for further characterization. Furthermore, while automated approaches have been developed, they are often limited in their accuracy, particularly for larger proteins. Here, we address this by introducing the software COMPASS, which, by combining automated resonance assignment with manual intervention, is able to achieve accuracy approaching that from manual assignments at greatly accelerated speeds. Moreover, by including the option to compensate for isotope shift effects in deuterated proteins, COMPASS is far more accurate for larger proteins than existing automated methods. COMPASS is an open-source project licensed under GNU General Public License and is available for download from http://www.liu.se/forskning/foass/tidigare-foass/patrik-lundstrom/software?l=en. Source code and binaries for Linux, Mac OS X and Microsoft Windows are available.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-115010 (URN)10.1371/journal.pcbi.1004022 (DOI)000349309400013 ()25569628 (PubMedID)
Note

Funding Agencies|Swedish Research Council [Dnr. 2012-5136]

Available from: 2015-03-09 Created: 2015-03-06 Last updated: 2017-12-04
2. Robust and convenient analysis of protein thermal and chemical stability
Open this publication in new window or tab >>Robust and convenient analysis of protein thermal and chemical stability
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2015 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, no 12, p. 2055-2062Article in journal (Refereed) Published
Abstract [en]

We present the software CDpal that is used to analyze thermal and chemical denaturation data to obtain information on protein stability. The software uses standard assumptions and equations applied to two-state and various types of three-state denaturation models in order to determine thermodynamic parameters. It can analyze denaturation monitored by both circular dichroism and fluorescence spectroscopy and is extremely flexible in terms of input format. Furthermore, it is intuitive and easy to use because of the graphical user interface and extensive documentation. As illustrated by the examples herein, CDpal should be a valuable tool for analysis of protein stability.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keywords
protein stability; thermal denaturation; chemical denaturation; circular dichroism; fluorescence; curve fitting; protein stability software; protein denaturation software
National Category
Chemical Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124648 (URN)10.1002/pro.2809 (DOI)000368292000014 ()26402034 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-5136]; LiU Cancer

Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2017-11-30
3. Comprehensive analysis of NMR data using advanced line shape fitting.
Open this publication in new window or tab >>Comprehensive analysis of NMR data using advanced line shape fitting.
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2017 (English)In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 69, no 2, p. 93-99Article in journal (Refereed) Published
Abstract [en]

NMR spectroscopy is uniquely suited for atomic resolution studies of biomolecules such as proteins, nucleic acids and metabolites, since detailed information on structure and dynamics are encoded in positions and line shapes of peaks in NMR spectra. Unfortunately, accurate determination of these parameters is often complicated and time consuming, in part due to the need for different software at the various analysis steps and for validating the results. Here, we present an integrated, cross-platform and open-source software that is significantly more versatile than the typical line shape fitting application. The software is a completely redesigned version of PINT ( https://pint-nmr.github.io/PINT/ ). It features a graphical user interface and includes functionality for peak picking, editing of peak lists and line shape fitting. In addition, the obtained peak intensities can be used directly to extract, for instance, relaxation rates, heteronuclear NOE values and exchange parameters. In contrast to most available software the entire process from spectral visualization to preparation of publication-ready figures is done solely using PINT and often within minutes, thereby, increasing productivity for users of all experience levels. Unique to the software are also the outstanding tools for evaluating the quality of the fitting results and extensive, but easy-to-use, customization of the fitting protocol and graphical output. In this communication, we describe the features of the new version of PINT and benchmark its performance.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
Dynamics, Line shape fitting, Peak integration, Relaxation, Spectral analysis
National Category
Biochemistry and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-142786 (URN)10.1007/s10858-017-0141-6 (DOI)000414206400004 ()29043470 (PubMedID)2-s2.0-85031497711 (Scopus ID)
Note

Funding agencies: Swedish Research Council [2012-5136]

Available from: 2017-11-03 Created: 2017-11-03 Last updated: 2017-12-04Bibliographically approved

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