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  1. Article ; Online: Potts Hamiltonian Models and Molecular Dynamics Free Energy Simulations for Predicting the Impact of Mutations on Protein Kinase Stability.

    Thakur, Abhishek / Gizzio, Joan / Levy, Ronald M

    The journal of physical chemistry. B

    2024  Volume 128, Issue 7, Page(s) 1656–1667

    Abstract: Single-point mutations in kinase proteins can affect their stability and fitness, and computational analysis of these effects can provide insights into the relationships among protein sequence, structure, and function for this enzyme family. To assess ... ...

    Abstract Single-point mutations in kinase proteins can affect their stability and fitness, and computational analysis of these effects can provide insights into the relationships among protein sequence, structure, and function for this enzyme family. To assess the impact of mutations on protein stability, we used a sequence-based Potts Hamiltonian model trained on a kinase family multiple-sequence alignment (MSA) to calculate the statistical energy (fitness) effects of mutations and compared these against relative folding free energies (ΔΔ
    MeSH term(s) Humans ; Molecular Dynamics Simulation ; Protein Kinases/genetics ; Thermodynamics ; Mutation ; Protein Stability ; Neoplasms
    Chemical Substances Protein Kinases (EC 2.7.-)
    Language English
    Publishing date 2024-02-13
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.3c08097
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.

    Gizzio, Joan / Thakur, Abhishek / Haldane, Allan / Levy, Ronald M

    Research square

    2024  

    Abstract: Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we ... ...

    Abstract Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory "folded" conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation "DFG-out Activation Loop Folded", is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes
    Language English
    Publishing date 2024-05-03
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-4048991/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.

    Gizzio, Joan / Thakur, Abhishek / Haldane, Allan / Post, Carol Beth / Levy, Ronald M

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we ... ...

    Abstract Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory "folded" conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation "DFG-out Activation Loop Folded", is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes
    Language English
    Publishing date 2024-05-02
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.08.584161
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases.

    Gizzio, Joan / Thakur, Abhishek / Haldane, Allan / Levy, Ronald M

    eLife

    2022  Volume 11

    Abstract: Inactive conformations of protein kinase catalytic domains where the DFG motif has a "DFG-out" orientation and the activation loop is folded present a druggable binding pocket that is targeted by FDA-approved 'type-II inhibitors' in the treatment of ... ...

    Abstract Inactive conformations of protein kinase catalytic domains where the DFG motif has a "DFG-out" orientation and the activation loop is folded present a druggable binding pocket that is targeted by FDA-approved 'type-II inhibitors' in the treatment of cancers. Tyrosine kinases (TKs) typically show strong binding affinity with a wide spectrum of type-II inhibitors while serine/threonine kinases (STKs) usually bind more weakly which we suggest here is due to differences in the folded to extended conformational equilibrium of the activation loop between TKs vs. STKs. To investigate this, we use sequence covariation analysis with a Potts Hamiltonian statistical energy model to guide absolute binding free-energy molecular dynamics simulations of 74 protein-ligand complexes. Using the calculated binding free energies together with experimental values, we estimated free-energy costs for the large-scale (~17-20 Å) conformational change of the activation loop by an indirect approach, circumventing the very challenging problem of simulating the conformational change directly. We also used the Potts statistical potential to thread large sequence ensembles over active and inactive kinase states. The structure-based and sequence-based analyses are consistent; together they suggest TKs evolved to have free-energy penalties for the classical 'folded activation loop' DFG-out conformation relative to the active conformation, that is, on average, 4-6 kcal/mol smaller than the corresponding values for STKs. Potts statistical energy analysis suggests a molecular basis for this observation, wherein the activation loops of TKs are more weakly 'anchored' against the catalytic loop motif in the active conformation and form more stable substrate-mimicking interactions in the inactive conformation. These results provide insights into the molecular basis for the divergent functional properties of TKs and STKs, and have pharmacological implications for the target selectivity of type-II inhibitors.
    MeSH term(s) Protein Serine-Threonine Kinases/metabolism ; Tyrosine ; Protein Kinase Inhibitors/pharmacology ; Molecular Dynamics Simulation ; Protein Conformation ; Threonine ; Serine
    Chemical Substances Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Tyrosine (42HK56048U) ; Protein Kinase Inhibitors ; Threonine (2ZD004190S) ; Serine (452VLY9402)
    Language English
    Publishing date 2022-12-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.83368
    Database MEDical Literature Analysis and Retrieval System OnLINE

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