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Article ; Online: Insights into the solubility of

Freites, J Alfredo / Louis, Mohab N / Tobias, Douglas J

2023 Volume 44, Issue 19, Page(s) 1658–1666

Abstract: The molecular basis underlying the rich phase behavior of globular proteins remains poorly understood. We use atomistic multiscale molecular simulations to model the solution-state conformational dynamics and interprotein interactions ... ...

Abstract	The molecular basis underlying the rich phase behavior of globular proteins remains poorly understood. We use atomistic multiscale molecular simulations to model the solution-state conformational dynamics and interprotein interactions of
MeSH term(s)	Humans ; gamma-Crystallins/chemistry ; gamma-Crystallins/metabolism ; Solubility ; Cataract/metabolism
Chemical Substances	gamma-Crystallins
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1479181-X
ISSN	1096-987X ; 0192-8651
ISSN (online)	1096-987X
ISSN	0192-8651
DOI	10.1002/jcc.27116
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Article ; Online: Multiscale Molecular Dynamics Simulations of an Active Self-Assembling Material.

Song, Yuanming / Selmani, Serxho / Freites, J Alfredo / Guan, Zhibin / Tobias, Douglas J

The journal of physical chemistry. B

2024 Volume 128, Issue 5, Page(s) 1266–1274

Abstract: Inspired by the adaptability observed in biological materials, self-assembly processes have attracted significant interest for their potential to yield novel materials with unique properties. However, experimental methods have often fallen short in ... ...

Abstract	Inspired by the adaptability observed in biological materials, self-assembly processes have attracted significant interest for their potential to yield novel materials with unique properties. However, experimental methods have often fallen short in capturing the molecular details of the assembly process. In this study, we employ a multiscale molecular dynamics simulation approach, complemented by NMR quantification, to investigate the mechanism of self-assembly in a redox-fueled bioinspired system. Contrary to conventional assumptions, we have uncovered a significant role played by the monomer precursor in the assembly process, with its presence varying with concentration and the extent of conversion of the monomer to the dimer. Experimental confirmation through NMR quantification underscores the concentration-dependent incorporation of monomers into the fibrous structures. Furthermore, our simulations also shed light on the diverse intermolecular interactions, including T-shaped and parallel π stacking, as well as hydrogen bonds, in stabilizing the aggregates. Overall, the open conformation of the dimer is preferred within these aggregates. However, inside the aggregates, the distribution of conformations shifts slightly to the closed conformation compared to on the surface. These findings contribute to the growing field of bioinspired materials science by providing valuable mechanistic and structural insights to guide the design and development of self-assembling materials with biomimetic functionalities.
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.3c06572
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Article ; Online: Network Hamiltonian Models for Unstructured Protein Aggregates, with Application to γD-Crystallin.

Diessner, Elizabeth M / Freites, J Alfredo / Tobias, Douglas J / Butts, Carter T

The journal of physical chemistry. B

2023 Volume 127, Issue 3, Page(s) 685–697

Abstract: ... variant W42R in solution, performed by Wong, E. K.; Prytkova, V.; Freites, J. A.; Butts, C. T.; Tobias, D ... J. Molecular Mechanism of Aggregation of the Cataract-Related γD-Crystallin W42R Variant ...

Abstract	Network Hamiltonian models (NHMs) are a framework for topological coarse-graining of protein-protein interactions, in which each node corresponds to a protein, and edges are drawn between nodes representing proteins that are noncovalently bound. Here, this framework is applied to aggregates of γD-crystallin, a structural protein of the eye lens implicated in cataract disease. The NHMs in this study are generated from atomistic simulations of equilibrium distributions of wild-type and the cataract-causing variant W42R in solution, performed by Wong, E. K.; Prytkova, V.; Freites, J. A.; Butts, C. T.; Tobias, D. J. Molecular Mechanism of Aggregation of the Cataract-Related γD-Crystallin W42R Variant from Multiscale Atomistic Simulations.
MeSH term(s)	Humans ; Intrinsically Disordered Proteins/metabolism ; Protein Aggregates ; gamma-Crystallins/chemistry ; Cataract/metabolism ; Lens, Crystalline/metabolism
Chemical Substances	Intrinsically Disordered Proteins ; Protein Aggregates ; gamma-Crystallins
Language	English
Publishing date	2023-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.2c07672
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Article ; Online: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain.

Manville, Rían W / Alfredo Freites, J / Sidlow, Richard / Tobias, Douglas J / Abbott, Geoffrey W

Nature communications

2023 Volume 14, Issue 1, Page(s) 3281

Abstract: There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka'wakw First Nations of the ... ...

Abstract	There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka'wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies.
MeSH term(s)	Humans ; Ataxia/drug therapy ; Ataxia/genetics ; Ion Channel Gating ; Kv1.1 Potassium Channel/genetics ; Kv1.1 Potassium Channel/metabolism ; Mutation ; Indigenous Canadians ; Medicine, Traditional
Chemical Substances	Kv1.1 Potassium Channel (147173-20-4)
Language	English
Publishing date	2023-06-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38834-6
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Article ; Online: Anomalous Diffusion of Peripheral Membrane Signaling Proteins from All-Atom Molecular Dynamics Simulations.

Geragotelis, Andrew D / Freites, J Alfredo / Tobias, Douglas J

The journal of physical chemistry. B

2021 Volume 125, Issue 35, Page(s) 9990–9998

Abstract: Peripheral membrane proteins bind transiently to membrane surfaces as part of many signaling pathways. The bound proteins perform two-dimensional (2-D) diffusion on the membrane surface during the recruitment function. To better understand the interplay ... ...

Abstract	Peripheral membrane proteins bind transiently to membrane surfaces as part of many signaling pathways. The bound proteins perform two-dimensional (2-D) diffusion on the membrane surface during the recruitment function. To better understand the interplay between the 2-D diffusion of these protein domains and their membrane binding modes, we performed multimicrosecond all-atom molecular dynamics simulations of two regulatory domains, a C2 domain and a pleckstrin homology (PH) domain, in their experimentally determined bound configuration to a lipid bilayer. The protein bound configurations are preserved throughout the simulation trajectories. Both protein domains exhibit anomalous diffusion with distinct features in their dynamics that reflect their different modes of binding. An analysis of their diffusive behavior reveals common features with the diffusion of lipid molecules in lipid bilayers, suggesting that the 2-D motion of protein domains bound to the membrane surface is modulated by the viscoelastic nature of the lipid bilayer.
MeSH term(s)	Cell Membrane ; Diffusion ; Lipid Bilayers ; Molecular Dynamics Simulation ; Pleckstrin Homology Domains
Chemical Substances	Lipid Bilayers
Language	English
Publishing date	2021-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.1c04905
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Article ; Online: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

Rían W. Manville / J. Alfredo Freites / Richard Sidlow / Douglas J. Tobias / Geoffrey W. Abbott

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 18

Abstract: Abstract There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations ... ...

Abstract	Abstract There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies.
Keywords	Science ; Q
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article: A β-barrel-like tetramer formed by a β-hairpin derived from Aβ.

Samdin, Tuan D / Jones, Chelsea R / Guaglianone, Gretchen / Kreutzer, Adam G / Freites, J Alfredo / Wierzbicki, Michał / Nowick, James S

Chemical science

2023 Volume 15, Issue 1, Page(s) 285–297

Abstract: β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers. Three different alignments of β-hairpins have been observed in the structures of Aβ oligomers or fibrils. Differences in β-hairpin alignment likely contribute to the ... ...

Abstract	β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers. Three different alignments of β-hairpins have been observed in the structures of Aβ oligomers or fibrils. Differences in β-hairpin alignment likely contribute to the heterogeneity of Aβ oligomers and thus impede their study at high-resolution. Here, we designed, synthesized, and studied a series of β-hairpin peptides derived from Aβ
Language	English
Publishing date	2023-11-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d3sc05185d
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Article ; Online: Thermodynamics and Mechanism of the Membrane Permeation of Hv1 Channel Blockers.

Lim, Victoria T / Freites, J Alfredo / Tombola, Francesco / Tobias, Douglas J

The Journal of membrane biology

2020 Volume 254, Issue 1, Page(s) 5–16

Abstract: The voltage-gated proton channel Hv1 mediates efflux of protons from the cell. Hv1 integrally contributes to various physiological processes including pH homeostasis and the respiratory burst of phagocytes. Inhibition of Hv1 may provide therapeutic ... ...

Abstract	The voltage-gated proton channel Hv1 mediates efflux of protons from the cell. Hv1 integrally contributes to various physiological processes including pH homeostasis and the respiratory burst of phagocytes. Inhibition of Hv1 may provide therapeutic avenues for the treatment of inflammatory diseases, breast cancer, and ischemic brain damage. In this work, we investigate two prototypical Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI), and 5-chloro-2-guanidinobenzimidazole (GBIC), from an experimentally screened class of guanidine derivatives. Both compounds block proton conduction by binding the same site located on the intracellular side of the channel. However, when added to the extracellular medium, the compounds strongly differ in their ability to inhibit proton conduction, suggesting substantial differences in membrane permeability. Here, we compute the potential of mean force for each compound to permeate through the membrane using atomistic molecular dynamics simulations with the adaptive biasing force method. Our results rationalize the putative distinction between these two blockers with respect to their abilities to permeate the cellular membrane.
MeSH term(s)	Cell Membrane Permeability ; Ion Channels/antagonists & inhibitors ; Ion Channels/metabolism ; Molecular Dynamics Simulation ; Protons ; Thermodynamics
Chemical Substances	Ion Channels ; Protons
Language	English
Publishing date	2020-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3082-x
ISSN	1432-1424 ; 0022-2631
ISSN (online)	1432-1424
ISSN	0022-2631
DOI	10.1007/s00232-020-00149-8
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Article ; Online: Experimental and Simulation Studies of Aquaporin 0 Water Permeability and Regulation.

Hall, James E / Freites, J Alfredo / Tobias, Douglas J

Chemical reviews

2019 Volume 119, Issue 9, Page(s) 6015–6039

Abstract: We begin with the history of aquaporin zero (AQP0), the most prevalent membrane protein in the eye lens, from the early days when AQP0 was a protein of unknown function known as Major Intrinsic Protein 26. We progress through its joining the aquaporin ... ...

Abstract	We begin with the history of aquaporin zero (AQP0), the most prevalent membrane protein in the eye lens, from the early days when AQP0 was a protein of unknown function known as Major Intrinsic Protein 26. We progress through its joining the aquaporin family as a water channel in its own right and discuss how regulation of its water permeability by pH and calcium came to be discovered experimentally and linked to lens homeostasis and development. We review the development of molecular dynamics (MD) simulations of lipid bilayers and membrane proteins, including aquaporins, with an emphasis on simulation studies that have elucidated the mechanisms of water conduction, selectivity, and proton exclusion by aquaporins in general. We also review experimental and theoretical progress toward understanding why mammalian AQP0 has a lower water permeability than other aquaporins and the evolution of our present understanding of how its water permeability is regulated by pH and calcium. Finally, we discuss how MD simulations have elucidated the nature of lipid interactions with AQP0.
MeSH term(s)	Animals ; Aquaporins/chemistry ; Aquaporins/metabolism ; Biological Transport ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Cell Membrane Permeability ; Eye Proteins/chemistry ; Eye Proteins/metabolism ; Humans ; Hydrogen-Ion Concentration ; Lipid Bilayers/chemistry ; Lipid Bilayers/metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Water/chemistry ; Water/metabolism
Chemical Substances	Aquaporins ; Eye Proteins ; Lipid Bilayers ; aquaporin 0 ; Water (059QF0KO0R)
Language	English
Publishing date	2019-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/acs.chemrev.9b00106
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Article ; Online: Voltage Sensing in Membranes: From Macroscopic Currents to Molecular Motions.

Freites, J Alfredo / Tobias, Douglas J

The Journal of membrane biology

2015 Volume 248, Issue 3, Page(s) 419–430

Abstract: Voltage-sensing domains (VSDs) are integral membrane protein units that sense changes in membrane electric potential, and through the resulting conformational changes, regulate a specific function. VSDs confer voltage-sensitivity to a large superfamily ... ...

Abstract	Voltage-sensing domains (VSDs) are integral membrane protein units that sense changes in membrane electric potential, and through the resulting conformational changes, regulate a specific function. VSDs confer voltage-sensitivity to a large superfamily of membrane proteins that includes voltage-gated Na[Formula: see text], K[Formula: see text], Ca[Formula: see text] ,and H[Formula: see text] selective channels, hyperpolarization-activated cyclic nucleotide-gated channels, and voltage-sensing phosphatases. VSDs consist of four transmembrane segments (termed S1 through S4). Their most salient structural feature is the highly conserved positions for charged residues in their sequences. S4 exhibits at least three conserved triplet repeats composed of one basic residue (mostly arginine) followed by two hydrophobic residues. These S4 basic side chains participate in a state-dependent internal salt-bridge network with at least four acidic residues in S1-S3. The signature of voltage-dependent activation in electrophysiology experiments is a transient current (termed gating or sensing current) upon a change in applied membrane potential as the basic side chains in S4 move across the membrane electric field. Thus, the unique structural features of the VSD architecture allow for competing requirements: maintaining a series of stable transmembrane conformations, while allowing charge motion, as briefly reviewed here.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Membrane/chemistry ; Cell Membrane/physiology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Ion Channel Gating ; Lipid Bilayers/chemistry ; Membrane Potentials ; Membrane Proteins/chemistry ; Models, Molecular ; Molecular Sequence Data ; Protein Structure, Secondary
Chemical Substances	Lipid Bilayers ; Membrane Proteins
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	3082-x
ISSN	1432-1424 ; 0022-2631
ISSN (online)	1432-1424
ISSN	0022-2631
DOI	10.1007/s00232-015-9805-x
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