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Multiscale method for modeling binding phenomena involving large objects: application to kinesin motor domains motion along microtubules.

ABSTRACT: Many biological phenomena involve the binding of proteins to a large object. Because the electrostatic forces that guide binding act over large distances, truncating the size of the system to facilitate computational modeling frequently yields inaccurate results. Our multiscale approach implements a computational focusing method that permits computation of large systems without truncating the electrostatic potential and achieves the high resolution required for modeling macromolecular interactions, all while keeping the computational time reasonable. We tested our approach on the motility of various kinesin motor domains. We found that electrostatics help guide kinesins as they walk: N-kinesins towards the plus-end, and C-kinesins towards the minus-end of microtubules. Our methodology enables computation in similar, large systems including protein binding to DNA, viruses, and membranes.

SUBMITTER: Li L

PROVIDER: S-EPMC4796874 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Multiscale method for modeling binding phenomena involving large objects: application to kinesin motor domains motion along microtubules.

Li Lin L Alper Joshua J Alexov Emil E

Scientific reports 20160318

Many biological phenomena involve the binding of proteins to a large object. Because the electrostatic forces that guide binding act over large distances, truncating the size of the system to facilitate computational modeling frequently yields inaccurate results. Our multiscale approach implements a computational focusing method that permits computation of large systems without truncating the electrostatic potential and achieves the high resolution required for modeling macromolecular interactio ...[more]

PMID: 26988596

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Project description:Kinesin motor proteins drive intracellular transport by coupling ATP hydrolysis to conformational changes that mediate directed movement along microtubules. Characterizing these distinct conformations and their interconversion mechanism is essential to determining an atomic-level model of kinesin action. Here we report a comprehensive principal component analysis of 114 experimental structures along with the results of conventional and accelerated molecular dynamics simulations that together map the structural dynamics of the kinesin motor domain. All experimental structures were found to reside in one of three distinct conformational clusters (ATP-like, ADP-like and Eg5 inhibitor-bound). These groups differ in the orientation of key functional elements, most notably the microtubule binding α4-α5, loop8 subdomain and α2b-β4-β6-β7 motor domain tip. Group membership was found not to correlate with the nature of the bound nucleotide in a given structure. However, groupings were coincident with distinct neck-linker orientations. Accelerated molecular dynamics simulations of ATP, ADP and nucleotide free Eg5 indicate that all three nucleotide states could sample the major crystallographically observed conformations. Differences in the dynamic coupling of distal sites were also evident. In multiple ATP bound simulations, the neck-linker, loop8 and the α4-α5 subdomain display correlated motions that are absent in ADP bound simulations. Further dissection of these couplings provides evidence for a network of dynamic communication between the active site, microtubule-binding interface and neck-linker via loop7 and loop13. Additional simulations indicate that the mutations G325A and G326A in loop13 reduce the flexibility of these regions and disrupt their couplings. Our combined results indicate that the reported ATP and ADP-like conformations of kinesin are intrinsically accessible regardless of nucleotide state and support a model where neck-linker docking leads to a tighter coupling of the microtubule and nucleotide binding regions. Furthermore, simulations highlight sites critical for large-scale conformational changes and the allosteric coupling between distal functional sites.

Dataset Information

Multiscale method for modeling binding phenomena involving large objects: application to kinesin motor domains motion along microtubules.

Publications

Multiscale method for modeling binding phenomena involving large objects: application to kinesin motor domains motion along microtubules.

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