Dube Dheeraj Prakashchand

University of California, San Diego

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Jagannath Mondal

TIFR Centre for Interdisciplinary Sciences

Subhojit Roy

University of California, San Diego

Leonardo A Parra‐Rivas

University of California, San Diego

Surajit Sengupta

TIFR Centre for Interdisciplinary Sciences

Brent Aulston

University of California, San Diego

Padmini Rangamani

University of California, San Diego

Kayalvizhi Madhivanan

University of California, San Diego

Navjeet Ahalawat

Chaudhary Charan Singh Haryana Agricultural University

Nicholas P. Boyer

University of California, San Diego

Kristen Branes‐Guerrero

University of California, San Diego

Cooperative Institutions

University of California, San Diego

TIFR Centre for Interdisciplinary Sciences

Tata Institute of Fundamental Research

Universidad Católica Santo Domingo

Research Network (United States)

Ben-Gurion University of the Negev

Arrowhead Pharmaceuticals (United States)

University of Wisconsin–Madison

UCLouvain

University of Hyderabad

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Spontaneous transmembrane pore formation by short-chain synthetic peptide

Biophysical Journal (2021)

Jaya Krishna Koneru Dube Dheeraj Prakashchand Namita Dube Pushpita Ghosh Jagannath Mondal

10.1016/j.bpj.2021.08.033

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Citations (6)

Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function

Neuron (2023)

Leonardo A Parra‐Rivas Kayalvizhi Madhivanan Brent Aulston Lina Wang Dube Dheeraj Prakashchand

Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn—thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.

Synucleinopathies

10.1016/j.neuron.2023.11.020

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Citations (48)

Fundamental Challenges and Outlook in Simulating Liquid–Liquid Phase Separation of Intrinsically Disordered Proteins

The Journal of Physical Chemistry Letters (2021)

Khandekar Jishan Bari Dube Dheeraj Prakashchand

Intrinsically disordered proteins (IDPs) populate an ensemble of dynamic conformations, making their structural characterization by experiments challenging. Many IDPs undergo liquid–liquid phase separation into dense membraneless organelles with myriad cellular functions. Multivalent interactions in low-complexity IDPs promote the formation of these subcellular coacervates. While solution NMR, Förster resonance energy transfer (FRET), and small-angle X-ray scattering (SAXS) studies on IDPs have their own challenges, recent computational methods draw a rational trade-off to characterize the driving forces underlying phase separation. In this Perspective, we critically evaluate the scope of approximation-free field theoretic simulations, well-tempered ensemble methods, enhanced sampling techniques, coarse-grained force fields, and slab simulation approaches to offer an improved understanding of phase separation. A synergy between simulation length scale and model resolution would reduce the existing caveats and enable theories of polymer physics to elucidate finer details of liquid–liquid phase separation (LLPS). These computational advances offer promise for rigorous characterization of the IDP proteome and designing peptides with tunable material and self-assembly properties.

Intrinsically Disordered Proteins

Characterization

Small-angle X-ray scattering

Scope (computer science)

10.1021/acs.jpclett.0c03404

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Citations (44)

Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic function

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Leonardo A Parra‐Rivas Kayalvizhi Madhivanan Lina Wang Nicholas P. Boyer Dube Dheeraj Prakashchand

Phosphorylation of α-synuclein at the Serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies, and also a therapeutic target. In physiologic states, only a small fraction of total α-syn is phosphorylated at this site, and consequently, almost all studies to date have focused on putative pathologic roles of this post-translational modification. We noticed that unlike native (total) α-syn that is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser-129 site blocked the ability of α-syn to attenuate activity-dependent synaptic vesicle (SV) recycling – widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments α-syn Ser-129P, and this phosphorylation is required for α-syn binding to VAMP2 and synapsin – two functional binding-partners that are necessary for α-syn function. AlphaFold2-driven modeling suggests a scenario where Ser129P induces conformational changes in the C-terminus that stabilizes this region and facilitates protein-protein interactions. Our experiments indicate that the pathology-associated Ser129P is an unexpected physiologic trigger of α-syn function, which has broad implications for pathophysiology and drug-development.

Synapsin

Synucleinopathies

Synapsin I

10.1101/2022.12.22.521485

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Citations (3)

Serine‐129 phosphorylation of α‐synuclein is a trigger for physiologic protein‐protein interactions and synaptic function

Alzheimer s & Dementia (2023)

Leonardo A Parra‐Rivas Kayalvizhi Madhivanan Lina Wang Nicholas P. Boyer Dube Dheeraj Prakashchand

Abstract Background α‐Synuclein (α‐syn) phosphorylation at the Serine‐129 (Ser129P) residue is a recognized pathologic hallmark of PD. Though only ∼4% of α‐syn is phosphorylated at this site under normal conditions, the tight endogenous regulation of α‐syn Ser129P suggests a physiologic role. Method We have use immunocytochemistry in cultured hippocampal neurons and immunohistochemistry in mouse brains to localize α‐syn Ser‐129P, optical pHluorin assays to report SV‐recycling and trafficking, multielectrode arrays (MEA) to examine neurotransmitter release, immunoprecitations and GST Pulldown assays to evaluate protein‐protein interactions, and AlphaFold2‐driven modeling to visualize how Ser129P induces conformational changes. Result We found that unlike native (total) α‐syn that is widely expressed throughout the brain, the overall pattern of α‐syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser‐129 site blocked the ability of α‐syn to attenuate activity‐dependent synaptic vesicle (SV) recycling – widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments α‐syn Ser‐129P, and this phosphorylation is required for α‐syn binding to VAMP2 and synapsin – two functional binding‐partners that are necessary for α‐syn function. AlphaFold2‐driven modeling suggests a scenario where Ser129P induces conformational changes in the C‐terminus that stabilizes this region and facilitates protein‐protein interactions. Conclusion Our data from cellular, in vivo, cell‐free systems, and molecular simulations strongly suggest that the pathology‐ associated Ser129 modification has a physiologic role at the synapse, which has broad implications for α‐syn pathophysiology and drug development.

Synapsin

Synapsin I

10.1002/alz.074269

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Citations (0)

Nonaffine Displacements Encode Collective Conformational Fluctuations in Proteins

Journal of Chemical Theory and Computation (2020)

Dube Dheeraj Prakashchand Navjeet Ahalawat Satyabrata Bandyopadhyay Surajit Sengupta Jagannath Mondal

Identifying subtle conformational fluctuations underlying the dynamics of biomacromolecules is crucial for resolving their free energy landscape. We show that a collective variable, originally proposed for crystalline solids, is able to filter out essential macromolecular motions more efficiently than other approaches. While homogeneous or "affine" deformations of the biopolymer are trivial, biopolymer conformations are complicated by the occurrence of inhomogeneous or "nonaffine" displacements of atoms relative to their positions in the native structure. We show that these displacements encode functionally relevant conformations of macromolecules, and in combination with a formalism based upon time-structured independent component analysis, they quantitatively resolve the free energy landscape of a number of macromolecules of hierarchical complexity. The kinetics of conformational transitions among the basins can now be mapped within the framework of a Markov state model. The nonaffine modes, obtained by projecting out homogeneous fluctuations from the local displacements, are found to be responsible for local structural changes required for transitioning between pairs of macrostates.

Energy landscape

Biopolymer

Formalism (music)

ENCODE

Conformational ensembles

10.1021/acs.jctc.9b01100

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Citations (8)

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

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Dube Dheeraj Prakashchand Navjeet Ahalawat Himanshu Khandelia Jagannath Mondal Surajit Sengupta

Abstract 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.

10.1101/342253

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Conformational Reorganization of Apolipoprotein E Triggered by Phospholipid Assembly

The Journal of Physical Chemistry B (2021)

Dube Dheeraj Prakashchand Jagannath Mondal

Apolipoprotein E (apoE), a major determinant protein for lipid metabolism, actively participates in lipid transport in the central nervous system via high-affinity interaction with the low-density lipoprotein receptor (LDLR). Prior evidences indicate that the phospholipids first need to assemble around apoE before the protein can recognize its receptor. However, despite multiple attempts via spectroscopic and biochemical investigations, it is unclear what are the impacts of lipid assembly on the globular structure of apoE. Here, using a combination of all-atom and coarse-grained molecular dynamics simulations, we demonstrate that an otherwise compact tertiary fold of monomeric apoE3 spontaneously unwraps in an aqueous phospholipid solution in two distinct stages. Interestingly, these structural reorganizations are triggered by an initial localized binding of lipid molecules to the C-terminal domain of the protein, which induce a rapid separation of the C-terminal domain of apoE3 from the rest of its tertiary fold. This is followed by a slow lipid-induced interhelix separation event within the N-terminal domain of the protein, as seen in an extensively long coarse-grained simulation. Remarkably, the resultant complex takes the shape of an "open conformation" of the lipid-stabilized unwrapped protein, which intriguingly coincides with an earlier proposal by a small-angle X-ray scattering (SAXS) experiment. The lipid-binding activity and the lipid-induced protein conformation are found to be robust across a monomeric mutant and wild-type sequence of apoE3. The "open" complex derived in coarse-grained simulation retains its structural morphology after reverse-mapping to the all-atom representation. Collectively, the investigation puts forward a plausible structure of currently elusive conformationally activated state of apoE3, which is primed for recognition by the lipoprotein receptor and can be exploited for eventual lipid transport.

Small-angle X-ray scattering

Apolipoprotein E

Protein tertiary structure

10.1021/acs.jpcb.1c03011

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Citations (4)

Conformational Reorganisation of Apolipoprotein E Triggered by Phospholipid Assembly

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Dube Dheeraj Prakashchand Jagannath Mondal

Apolipoprotein E ( ApoE), a major determinant protein for lipid-metabolism, actively participates in lipid transport in central nervous system via high-affinity interaction with lipoprotein receptor LDLR. Prior evidences indicate that the phospholipids first need to assemble around apoE, before the protein can recognise its receptor. However, despite multiple attempts via spectroscopic and biochemical investigations, it is unclear what are the impact of lipid assembly on globular structure of apoE. Here, using a combination of all-atom and coarse-grained molecular dynamics simulations, we demonstrate that, an otherwise compact tertiary fold of monomeric apoE3 spontaneously unwraps in an aqueous phospholipid solution in two distinct stages. Interestingly, these structural reorganizations are triggered by an initial localised binding of lipid molecules to the C-terminal domain of the protein, which induce a rapid separation of C-terminal domain of apoE3 from the rest of its tertiary fold. This is followed by a slow lipid-induced inter-helix separation event within the N-terminal domain of the protein, as seen in an extensively long coarse-grained simulation. Remarkably, the resultant complex takes the shape of an `open conformation' of lipid-stabilised unwrapped protein, which intriguingly coincides with an earlier proposal by small-angle X-ray scattering (SAXS) experiment. The lipid-binding activity and the lipid-induced protein conformation are found to be robust across a monomeric mutant and wild-type sequence of apoE3. The `open' complex derived in coarse-grained simulation retains its structural morphology after reverse-mapping to all-atom representation. Collectively, the investigation puts forward a plausible structure of currently elusive conformationally activated state of apoE3, which is primed for recognition by lipoprotein receptor and can be exploited for eventual lipid transport.

Small-angle X-ray scattering

Apolipoprotein E

Protein tertiary structure

10.1101/2020.08.18.255299

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Citations (0)

Non-affine displacements encode collective conformational fluctuations in proteins

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Dube Dheeraj Prakashchand Navjeet Ahalawat Satyabrata Bandyopadhyay Surajit Sengupta Jagannath Mondal

Abstract Identifying subtle conformational fluctuations underlying the dynamics of bio macro-molecules is crucial for resolving their free energy landscape. We show that a collective variable, originally proposed for crystalline solids, is able to filter out essential macro-molecular motions more efficiently than other approaches. While homogenous or ‘affine’ deformations of the biopolymer are trivial, biopolymer conformations are complicated by the occurrence of in-homogenous or ‘non-affine’ displacements of atoms relative to their positions in the native structure. We show that these displacements encode functionally relevant conformations of macromolecule and, in combination with a formalism based upon time-structured independent component analysis, quantitatively resolve the free energy landscape of a number of macromolecules of hierarchical complexity. The kinetics of conformational transitions among the basins can now be mapped within the framework of a Markov state model. The non-affine modes, obtained by projecting out homogenous fluctuations from the local displacements, are found to be responsible for local structural changes required for transitioning between pairs of macro states.

Energy landscape

ENCODE

Biopolymer

Conformational ensembles

Formalism (music)

10.1101/840850

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Citations (0)