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Georgoulia, Panagiota S.ORCID iD iconorcid.org/0000-0003-4573-8052
Publications (2 of 2) Show all publications
Georgoulia, P. S. & Glykos, N. M. (2019). Molecular simulation of peptides coming of age: accurate prediction of folding, dynamics and structures. Archives of Biochemistry and Biophysics, 664(March), 76-88
Open this publication in new window or tab >>Molecular simulation of peptides coming of age: accurate prediction of folding, dynamics and structures
2019 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 664, no March, p. 76-88Article in journal (Refereed) Published
Abstract [en]

The application of molecular dynamics simulations to study the folding and dynamics of peptides has attracted a lot of interest in the last couple of decades. Following the successful prediction of the folding of several proteins using molecular simulation, foldable peptides emerged as a favourable system mainly due to their application in improving protein structure prediction methods and in drug design studies. However, their performance is inherently linked to the accuracy of the empirical force fields used in the simulations, whose optimisation and validation is of paramount importance. Here we review the most important findings in the field of molecular peptide simulations and highlight the significant advancements made over the last twenty years. Special reference is made on the simulation of disordered peptides and the remaining challenge to find a force field able to describe accurately their conformational landscape.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Peptide simulations, Peptide folding, Peptide dynamics, Empirical force fields, Validation
National Category
Bioinformatics (Computational Biology) Biochemistry and Molecular Biology
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-81246 (URN)10.1016/j.abb.2019.01.033 (DOI)000461411200009 ()30711540 (PubMedID)2-s2.0-85061034821 (Scopus ID)
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-08-29Bibliographically approved
Georgoulia, P. S., Todde, G., Bjelic, S. & Friedman, R. (2019). The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia. Biochimica et Biophysica Acta - General Subjects, 1863(4), 732-741
Open this publication in new window or tab >>The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia
2019 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, no 4, p. 732-741Article in journal (Refereed) Published
Abstract [en]

Background

Abl1 is a protein tyrosine kinase whose aberrant activation due to mutations is the culprit of several cancers, most notably chronic myeloid leukaemia. Several Abl1 inhibitors are used as anti-cancer drugs. Unfortunately, drug resistance limits their effectiveness. The main cause for drug resistance is mutations in the kinase domain (KD) of Abl1 that evolve in patients. The T315I mutation confers resistance against all clinically-available inhibitors except ponatinib. Resistance to ponatinib can develop by compound (double) mutations.

Methods

Kinetic measurements of the KD of Abl1 and its mutants were carried out to examine their catalytic activity. Specifically, mutants that lead to drug resistance against ponatinib were considered. Molecular dynamics simulations and multiple sequence analysis were used for explanation of the experimental findings.

Results

The catalytic efficiency of the T315I pan-resistance mutant is more than two times lower than that of the native KD. All ponatinib resistant mutations restore the catalytic efficiency of the enzyme. Two of them (G250E/T315I and Y253H/E255V) have a catalytic efficiency that is more than five times that of the native KD.

Conclusions

The measurements and analysis suggest that resistance is at least partially due to the development of a highly efficient kinase through subsequent mutations. The simulations highlight modifications in two structurally important regions of Abl1, the activation and phosphate binding loops, upon mutations.

General significance

Experimental and computational methods were used together to explain how mutations in the kinase domain of Abl1 lead to resistance against the most advanced drug currently in use to treat chronic myeloid leukaemia.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Biophysics Theoretical Chemistry Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences; Natural Science, Chemistry; Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-80308 (URN)10.1016/j.bbagen.2019.01.011 (DOI)000460853200009 ()30684523 (PubMedID)2-s2.0-85060896659 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2019-08-29Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4573-8052

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