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Todde, G. & Friedman, R. (2019). Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition. Journal of Physical Chemistry B, 123(26), 5385-5394
Open this publication in new window or tab >>Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition
2019 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, no 26, p. 5385-5394Article in journal (Refereed) Published
Abstract [en]

The aberrant expression of kinases is often associated with pathologies such as cancer and autoimmune diseases. Like other types of enzymes, kinases can adopt active and inactive states, where a shift toward more stable active state often leads to disease. Dozens of kinase inhibitors are, therefore, used as drugs. Most of these bind to either the inactive or active state. In this work, we study the transitions between these two states in FLT3, an important drug target in leukemias. Kinases are composed of two lobes (N- and C-terminal lobes) with the catalytic site in-between. Through projection of the largest motions obtained through molecular dynamics (MD) simulations, we show that each of the end-states (active or inactive) already possess the ability for transition as the two lobes rotate which initiates the transition. A targeted simulation approach known as essential dynamics sampling (EDS) was used to speed up the transition between the two protein states. Coupling the EDS to implicit-solvent MD was performed to estimate the free energy barriers of the transitions. The activation energies were found in good agreement with previous estimates obtained for other kinases. Finally, we identified FLT3 intermediates that assumed configurations that resemble that of the c-Src nonreceptor tyrosine kinase. The intermediates show better binding to the drug ponatinib than c-Src and the inactive state of FLT3. This suggests that targeting intermediate states can be used to explain the drug-binding patterns of kinases and for rational drug design.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Theoretical Chemistry Physical Chemistry Biophysics
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-86904 (URN)10.1021/acs.jpcb.9b01567 (DOI)000474796300001 ()31244095 (PubMedID)
Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-25Bibliographically approved
Todde, G. & Friedman, R. (2019). Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains. Physical Chemistry, Chemical Physics - PCCP, 21(34), 18467-18476
Open this publication in new window or tab >>Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains
2019 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 21, no 34, p. 18467-18476Article in journal (Refereed) Published
Abstract [en]

he aberrant expression of FLT3 tyrosine kinase is associated primarily with acute myeloid leukaemia. This blood malignancy is often related to the onset of internal tandem duplications (ITDs) in the native sequence of the protein. The ITDs occur mainly in the juxtamembrane domain of the protein and alter the normal activity of the enzyme. In this work, we have studied the native form of FLT3 and six mutants by molecular dynamics simulations. The catalytic activity of FLT3 is exerted by the tyrosine kinase domain (KD) and regulated by the juxtamembrane (JM) domain. Analysis of the dynamics of these two domains have shown that the introduction of ITDs in the JM domain alters both structural and dynamic parameters. The presence of ITDs allowed the protein to span a larger portion of the conformational space, particularly in the JM domain and the activation loop. The FLT3 mutants were found to adopt more stable configurations than the native enzyme. This was due to the different arrangements assumed by the JM domain. Larger fluctuations of the activation loop were found in four of the six mutants. In the native FLT3, the key residue Tyr(572) is involved in a strong and stable interaction with an ion pair. This interaction, which is thought to keep the JM in place hence regulating the activity of the enzyme, was found to break in all FLT3 mutants.

Place, publisher, year, edition, pages
Royal Society of Medicine Press, 2019
National Category
Theoretical Chemistry Physical Chemistry Biophysics
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-88817 (URN)10.1039/C9CP02938A (DOI)000483701200033 ()
Funder
Swedish Cancer Society, CAN 2015/387Swedish Cancer Society, CAN 2018/362Swedish National Infrastructure for Computing (SNIC), 2018/3-46Swedish National Infrastructure for Computing (SNIC), 2018/3-47Swedish National Infrastructure for Computing (SNIC), 2019/3-29
Available from: 2019-08-28 Created: 2019-08-28 Last updated: 2019-09-25Bibliographically approved
Steinz, M. M., Persson, M., Aresh, B., Olsson, K., Cheng, A. J., Ahlstrand, E., . . . Lanner, J. T. (2019). Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. JCI Insight, 4(9), 1-16, Article ID e126347.
Open this publication in new window or tab >>Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis
Show others...
2019 (English)In: JCI Insight, ISSN 2324-7703, Vol. 4, no 9, p. 1-16, article id e126347Article in journal (Refereed) Published
Abstract [en]

Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here we show that oxidative post-translational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic simulations revealed that these areas, here coined “hotspots”, are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.

Place, publisher, year, edition, pages
American Society for Clinical Investigation, 2019
National Category
Physiology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-82024 (URN)10.1172/jci.insight.126347 (DOI)000466814100015 ()2-s2.0-85070659458 (Scopus ID)
Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-08-29Bibliographically approved
Friedman, R. (2019). Simulations of Biomolecules in Electrolyte Solutions. Advanced Theory and Simulations, 2(4), 1-10, Article ID 1800163.
Open this publication in new window or tab >>Simulations of Biomolecules in Electrolyte Solutions
2019 (English)In: Advanced Theory and Simulations, E-ISSN 2513-0390, Vol. 2, no 4, p. 1-10, article id 1800163Article in journal (Refereed) Published
Abstract [en]

Biomolecules including proteins, lipid membranes, and nucleic acids operate at an aqueous milieu that includes solvated ions. The interactions with ions affect biomolecules in different ways depending on the nature of the solute and the type of the ions. The dynamic nature of small soluble ions makes it difficult to follow them by structural methods. Consequently, theories were developed to explain how biomolecules interact in an environment that includes electrolytes. Moreover, simulations studies are often used to study such systems at the molecular or atomistic level. The status of the field, and inparticular of simulation studies, is the subject of this progress report.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
National Category
Theoretical Chemistry
Research subject
Natural Science, Chemistry
Identifiers
urn:nbn:se:lnu:diva-79570 (URN)10.1002/adts.201800163 (DOI)000463986600005 ()
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-04-30Bibliographically approved
Friedman, R. (2019). Specific Ion and Concentration Effects in Acetate Solutions with Na+, K+ and Cs+. ChemPhysChem, 20(8), 1006-1010
Open this publication in new window or tab >>Specific Ion and Concentration Effects in Acetate Solutions with Na+, K+ and Cs+
2019 (English)In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 20, no 8, p. 1006-1010Article in journal (Refereed) Published
Abstract [en]

How salt ions affect solutes and the water beyond the solvation shell is not well understood. Molecular dynamics simulations of alkali-acetate solutions were analysed here in order to examine if, and how, different cations and solute concentrations affect the water structure and the interactions between water and acetates. The results revealed that water structure is perturbed to more than 1 nm away from the acetates and that this effect is more pronounced in physiological than in molar electrolyte concentrations. Analysis of simulations of a soluble protein revealed that the water orientation is perturbed to at least 1.5 nm from the protein structure. Furthermore, modifications to the orientation of water around carboxylate side chains were shown to depend on the local environment on the protein surface, and could extend to well over 1 nm, which may have an effect on protein dynamics during MD simulations in small water boxes.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
electrolyte solutions, Hofmeister effects, ion pairs, molecular dynamics, water structure
National Category
Physical Chemistry
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-82413 (URN)10.1002/cphc.201900163 (DOI)000465034500003 ()30817057 (PubMedID)2-s2.0-85063595612 (Scopus ID)
Available from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-08-29Bibliographically approved
Lindström, J., de Wijn, A. S. & Friedman, R. (2019). Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia. BMC Cancer, 19, 1-13, Article ID 508.
Open this publication in new window or tab >>Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia
2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, p. 1-13, article id 508Article in journal (Refereed) Published
Abstract [en]

BackgroundResistance towards targeted cancer treatments caused by single nucleotide variations is a major issue in many malignancies. Currently, there are a number of available drugs for chronic myeloid leukaemia (CML), which are overcome by different sets of mutations. The main aim of this study was to explore if it can be possible to exploit this and create a treatment protocol that outperforms each drug on its own.MethodsWe present a computer program to test different treatment protocols against CML, based on available resistance mutation growth data. The evolution of a relatively stable pool of cancer stem cells is modelled as a stochastic process, with the growth of cells expressing a tumourigenic protein (here, Abl1) and any emerging mutants determined principally by the drugs used in the therapy.ResultsThere can be some benefit to Bosutinib-Ponatinib rotation therapy even if the mutation status is unknown, whereas Imatinib-Nilotinib rotation is unlikely to improve the outcomes. Furthermore, an interplay between growth inhibition and selection effects generates a non-linear relationship between drug doses and the risk of developing resistance.ConclusionsDrug rotation therapy might be able to delay the onset of resistance in CML patients without costly ongoing observation of mutation status. Moreover, the simulations give credence to the suggestion that lower drug concentrations may achieve better results following major molecular response in CML.

Place, publisher, year, edition, pages
BioMed Central, 2019
National Category
Bioinformatics and Systems Biology Cancer and Oncology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-84416 (URN)10.1186/s12885-019-5690-5 (DOI)000469322800004 ()31138173 (PubMedID)2-s2.0-85066397867 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2019-05-29 Created: 2019-05-29 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
Buetti-Dinh, A., Jensen, R. & Friedman, R. (2018). A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy. BMC Cancer, 18(1), 1-8, Article ID 569.
Open this publication in new window or tab >>A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy
2018 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, no 1, p. 1-8, article id 569Article in journal (Refereed) Published
Abstract [en]

Background: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. Methods: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors. Results: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and P13K appeared as a significant factor in controlling tumour proliferation. Conclusions: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

Place, publisher, year, edition, pages
BioMed Central, 2018
National Category
Cancer and Oncology Bioinformatics and Systems Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-76627 (URN)10.1186/s12885-018-4451-1 (DOI)000432706500002 ()29776351 (PubMedID)2-s2.0-85047067972 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2018-07-03 Created: 2018-07-03 Last updated: 2019-08-29Bibliographically approved
Ahlstrand, E., Buetti-Dinh, A. & Friedman, R. (2018). An interactive computer lab of the galvanic cell for students in biochemistry. Biochemistry and molecular biology education, 46(1), 58-65
Open this publication in new window or tab >>An interactive computer lab of the galvanic cell for students in biochemistry
2018 (English)In: Biochemistry and molecular biology education, ISSN 1470-8175, E-ISSN 1539-3429, Vol. 46, no 1, p. 58-65Article in journal (Refereed) Published
Abstract [en]

We describe an interactive module that can be used to teach basic concepts in electrochemistry and thermodynamics to first year natural science students. The module is used together with an experimental laboratory and improves the students’ understanding of thermodynamic quantities such as ΔrG, ΔrH, and ΔrS that are calculated but not directly measured in the lab. We also discuss how new technologies can substitute some parts of experimental chemistry courses, and improve accessibility to course material. Cloud computing platforms such as CoCalc facilitate the distribution of computer codes and allow students to access and apply interactive course tools beyond the course's scope. Despite some limitations imposed by cloud computing, the students appreciated the approach and the enhanced opportunities to discuss study questions with their classmates and instructor as facilitated by the interactive tools. 

Place, publisher, year, edition, pages
Wiley-Blackwell, 2018
National Category
Educational Sciences
Research subject
Natural Science, Science Education
Identifiers
urn:nbn:se:lnu:diva-69198 (URN)10.1002/bmb.21091 (DOI)000419876100007 ()29131508 (PubMedID)2-s2.0-85040649707 (Scopus ID)
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2019-08-29Bibliographically approved
Buetti-Dinh, A. & Friedman, R. (2018). Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK6. BMC Bioinformatics, 19, 1-13, Article ID 155.
Open this publication in new window or tab >>Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK6
2018 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, p. 1-13, article id 155Article in journal (Refereed) Published
Abstract [en]

Background

Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies.

Results

Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone.

Conclusions

The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.

Place, publisher, year, edition, pages
London: BioMed Central, 2018
National Category
Bioinformatics and Systems Biology Biochemistry and Molecular Biology Cancer and Oncology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-73804 (URN)10.1186/s12859-018-2145-y (DOI)000431025900001 ()29699481 (PubMedID)2-s2.0-85046037732 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2019-08-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8696-3104

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