On identifying collective displacements in apo-proteins that reveal eventual binding pathways

Dheeraj Dube, Navjeet Ahalawat, Himanshu Khandelia, Jagannath Mondal, Surajit Sengupta

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Resumé

Binding of small molecules to proteins often involves large conformational changes in the latter, which open up pathways to the binding site. Observing and pinpointing these rare events in large scale, all-atom, computations of specific protein-ligand complexes, is expensive and to a great extent serendipitous. Further, relevant collective variables which characterise specific binding or un-binding scenarios are still difficult to identify despite the large body of work on the subject. Here, we show that possible primary and secondary binding pathways can be discovered from short simulations of the apo-protein without waiting for an actual binding event to occur. We use a projection formalism, introduced earlier to study deformation in solids, to analyse local atomic displacements into two mutually orthogonal subspaces-those which are "affine" i.e. expressible as a homogeneous deformation of the native structure, and those which are not. The susceptibility to non-affine displacements among the various residues in the apo- protein is then shown to correlate with typical binding pathways and sites crucial for allosteric modifications. We validate our observation with all-atom computations of three proteins, T4-Lysozyme, Src kinase and Cytochrome P450.

OriginalsprogEngelsk
Artikelnummere1006665
TidsskriftPloS Computational Biology
Vol/bind15
Udgave nummer1
ISSN1553-734X
DOI
StatusUdgivet - jan. 2019

Fingeraftryk

Pathway
Proteins
Protein
protein
proteins
Atoms
Binding sites
Muramidase
lysozyme
cytochrome P-450
Cytochrome P-450 Enzyme System
ligand
cytochrome
binding sites
Rare Events
phosphotransferases (kinases)
Enzymes
Ligands
Observation
Susceptibility

Citer dette

Dube, Dheeraj ; Ahalawat, Navjeet ; Khandelia, Himanshu ; Mondal, Jagannath ; Sengupta, Surajit. / On identifying collective displacements in apo-proteins that reveal eventual binding pathways. I: PloS Computational Biology. 2019 ; Bind 15, Nr. 1.
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On identifying collective displacements in apo-proteins that reveal eventual binding pathways. / Dube, Dheeraj; Ahalawat, Navjeet; Khandelia, Himanshu; Mondal, Jagannath; Sengupta, Surajit.

I: PloS Computational Biology, Bind 15, Nr. 1, e1006665, 01.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - On identifying collective displacements in apo-proteins that reveal eventual binding pathways

AU - Dube, Dheeraj

AU - Ahalawat, Navjeet

AU - Khandelia, Himanshu

AU - Mondal, Jagannath

AU - Sengupta, Surajit

PY - 2019/1

Y1 - 2019/1

N2 - Binding of small molecules to proteins often involves large conformational changes in the latter, which open up pathways to the binding site. Observing and pinpointing these rare events in large scale, all-atom, computations of specific protein-ligand complexes, is expensive and to a great extent serendipitous. Further, relevant collective variables which characterise specific binding or un-binding scenarios are still difficult to identify despite the large body of work on the subject. Here, we show that possible primary and secondary binding pathways can be discovered from short simulations of the apo-protein without waiting for an actual binding event to occur. We use a projection formalism, introduced earlier to study deformation in solids, to analyse local atomic displacements into two mutually orthogonal subspaces-those which are "affine" i.e. expressible as a homogeneous deformation of the native structure, and those which are not. The susceptibility to non-affine displacements among the various residues in the apo- protein is then shown to correlate with typical binding pathways and sites crucial for allosteric modifications. We validate our observation with all-atom computations of three proteins, T4-Lysozyme, Src kinase and Cytochrome P450.

AB - Binding of small molecules to proteins often involves large conformational changes in the latter, which open up pathways to the binding site. Observing and pinpointing these rare events in large scale, all-atom, computations of specific protein-ligand complexes, is expensive and to a great extent serendipitous. Further, relevant collective variables which characterise specific binding or un-binding scenarios are still difficult to identify despite the large body of work on the subject. Here, we show that possible primary and secondary binding pathways can be discovered from short simulations of the apo-protein without waiting for an actual binding event to occur. We use a projection formalism, introduced earlier to study deformation in solids, to analyse local atomic displacements into two mutually orthogonal subspaces-those which are "affine" i.e. expressible as a homogeneous deformation of the native structure, and those which are not. The susceptibility to non-affine displacements among the various residues in the apo- protein is then shown to correlate with typical binding pathways and sites crucial for allosteric modifications. We validate our observation with all-atom computations of three proteins, T4-Lysozyme, Src kinase and Cytochrome P450.

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