John E. Straub
· ProfessorVerifiedBoston University · Chemistry
Active 1928–2026
About
Professor John E. Straub is a faculty member at Boston University, where he leads the Straub Lab. His research group focuses on the biophysical and computational study of amyloid proteins and their aggregation processes. The lab investigates the structure, stability, and formation mechanisms of amyloid fibrils, including those formed by Serum Amyloid A protein and amyloid-beta peptides. Research in the group also explores the role of hydration, polyanions, and membrane interactions in amyloid formation and protein-protein association. The lab employs a range of modeling approaches, from all-atom simulations to coarse-grained and lattice models, to understand the thermodynamics and kinetics underlying protein aggregation and phase separation in lipid mixtures. Professor Straub's group also develops algorithms to elucidate optimal transition pathways and studies the effects of membrane friction on molecular isomerization, contributing to the understanding of tension-based probes in biophysical systems.
Research topics
- Computer Science
- Chemistry
- Artificial Intelligence
- Neuroscience
- Computational chemistry
- Molecular physics
- Chemical physics
- Organic chemistry
- Pathology
- Biology
- Physical chemistry
- Quantum mechanics
- Medicine
- Algorithm
- Biochemistry
Selected publications
Zenodo (CERN European Organization for Nuclear Research) · 2026-03-30
datasetOpen accessSenior authorThis archive contains data for the publication "Accurate determination of the preferred aggregation number of a micelle-encapsulated membrane protein dimer" accepted following peer review on March 30, 2026 in Biophysical Journal.
Water‐Mediated Phosphoryl Wires Stabilize Pathological Tau Fibrils
Angewandte Chemie International Edition · 2026-05-23
articleOpen accessABSTRACT Hyperphosphorylation of tau is a hallmark of tauopathies, with specific phosphorylation sites elevated in pathological fibrils. However, the molecular role of this post‐translational modification (PTM) in driving tau aggregation remains unclear. In‐register fibril assembly places phosphoryl groups on adjacent monomers at ∼4.8 Å spacing, requiring an energetically favorable arrangement. Conventional intuition holds that closely packed phosphoryl groups should be electrostatically unfavorable. We test the opposing hypothesis: that phosphoryl groups within the fibril core associate into an extended “wire” that stabilizes the amyloid fibril. We examined two phosphorylation sites linked to neurodegeneration, serine 305 (S305 p ) and tyrosine 310 (Y310 p ), using seeding‐competent fibrils of the tau peptide jR2R3‐P301L. Multiple‐quantum spin counting (MQ‐SC) by 3 1 P solid‐state NMR with dynamic nuclear polarization (DNP) revealed at least six phosphorus spins linearly arranged within a protofibril, consistent with a MQ coherence order of four. Molecular dynamics simulations identified water‐mediated phosphoryl wire geometries, and 2D 1 H– 3 1 P heteronuclear correlation NMR confirmed water‐bridged phosphoryl‐phosphoryl contacts. Denaturation experiments showed that S305 phosphorylation increased fibril stability relative to the unmodified peptide. These findings show that phosphorylation within the tau fibril core promotes fibril registry and stability through water‐mediated, hydrogen‐bonded phosphoryl wires, which may be a structural signature for next‐generation pathological tau binders.
Structural and mechanistic characterization of heparin interactions with tau fibrils
Journal of Biological Chemistry · 2026-01-12
articleOpen accessSenior authorSoluble microtubule-associated tau protein can misfold and assemble into stable, insoluble amyloid fibrils. The accumulation of tau amyloid fibrils within neurons is a primary feature in the progression of neurodegenerative diseases, including Alzheimer's disease. Tau fibrils have been observed to colocalize with glycosaminoglycans, such as heparan sulfate (HS), in vivo. Heparin is a highly sulfated analog of HS that has been commonly used in vitro to accelerate tau aggregation. The binding of heparin to tau fibrils inhibits fibril uptake by neighboring cells, whereas HS on the cell surface modulates this uptake. Understanding the molecular interactions of heparin and HS with tau fibrils is important in developing therapeutic targets that can slow the progression of neurodegeneration. In this multiscale computational study, we employ a combination of Brownian dynamics and molecular dynamics to simulate heparin binding to two tau fibril polymorphic structures. Our simulations lead to the de novo prediction of heparin binding to basic residue ladders organized along the tau fibril axis. The mechanism of binding is facilitated by long-range electrostatic steering of the polyanionic heparin to the tau fibril surface, followed by the refinement of favorable short-range heparin-tau interactions. The identified binding sites are located in regions of excess densities in cryo-EM maps of the tau fibrils, providing support for the computational predictions. Our findings provide a structural and mechanistic framework for a better understanding of fibril-glycan interactions and how they influence the overall mechanism of tau fibril propagation.
The scientific legacy of Martin Karplus from the perspective of his collaborators
Biophysical Journal · 2026-04-01
articleZenodo (CERN European Organization for Nuclear Research) · 2026-01-08
datasetOpen accessThis archive contains data for the publication "Free Energy of Collagen-Mimetic Peptide Dimerization and Implications for Fibrillization" accepted following peer review on January 8, 2026 in Biophysical Journal.
Zenodo (CERN European Organization for Nuclear Research) · 2026-03-30
datasetOpen accessSenior authorThis archive contains data for the publication "Accurate determination of the preferred aggregation number of a micelle-encapsulated membrane protein dimer" accepted following peer review on March 30, 2026 in Biophysical Journal.
Open MIND · 2026-01-08
datasetThis archive contains data for the publication "Free Energy of Collagen-Mimetic Peptide Dimerization and Implications for Fibrillization" accepted following peer review on January 8, 2026 in Biophysical Journal.
Free energy of collagen-mimetic peptide dimerization and implications for fibrillization
Biophysical Journal · 2026-01-01
articleOpen accessProper assembly of collagen fibrils is essential, as they constitute a plurality of protein mass and structure in extracellular matrices. However, the molecular determinants of the collagen fibrillization mechanism are difficult to characterize, in part due to the size and heterogeneity of the collagen triple helix. We have used MD simulations to characterize the dimerization free energy landscape of model collagen-mimetic peptide triple helices. Under in vivo buffer conditions, we find that domains consisting purely of proline-hydroxyproline-glycine (POG) repeats readily dimerize via a tight hydrophobic association stabilized via additional hydrogen bonds involving hydroxyprolines (Hyp). For a model heterotrimeric triple helix optimized for stability using salt bridges, we find a much weaker association free energy minimum between triple helices. Notably, interstrand salt bridges within each triple helix do not readily break upon the encounter of two triple helices, and these longer side chains also block hydrophobic and Hyp-Hyp hydrogen-bonded interactions. In contrast, we find that a "charge zipper" sequence, designed to avoid intrahelix and promote interhelix salt bridges, forms dimers that are more than twice as stable as associations of POG-repeat triple helices. These results reveal that there are multiple modes of association of collagen triple helices that appear, to a large extent, orthogonal. Analysis of fibrillar collagens shows that, whereas charged residues are typically expected to drive fibrillization, approximately one-fourth of charged residues are involved in salt bridges within triple helices and may effectively be unavailable for participation in helix-helix interactions and interactions with other proteins in extracellular matrices.
Water‐Mediated Phosphoryl Wires Stabilize Pathological Tau Fibrils
Angewandte Chemie · 2026-05-23
articleOpen accessABSTRACT Hyperphosphorylation of tau is a hallmark of tauopathies, with specific phosphorylation sites elevated in pathological fibrils. However, the molecular role of this post‐translational modification (PTM) in driving tau aggregation remains unclear. In‐register fibril assembly places phosphoryl groups on adjacent monomers at ∼4.8 Å spacing, requiring an energetically favorable arrangement. Conventional intuition holds that closely packed phosphoryl groups should be electrostatically unfavorable. We test the opposing hypothesis: that phosphoryl groups within the fibril core associate into an extended “wire” that stabilizes the amyloid fibril. We examined two phosphorylation sites linked to neurodegeneration, serine 305 (S305 p ) and tyrosine 310 (Y310 p ), using seeding‐competent fibrils of the tau peptide jR2R3‐P301L. Multiple‐quantum spin counting (MQ‐SC) by 3 1 P solid‐state NMR with dynamic nuclear polarization (DNP) revealed at least six phosphorus spins linearly arranged within a protofibril, consistent with a MQ coherence order of four. Molecular dynamics simulations identified water‐mediated phosphoryl wire geometries, and 2D 1 H– 3 1 P heteronuclear correlation NMR confirmed water‐bridged phosphoryl‐phosphoryl contacts. Denaturation experiments showed that S305 phosphorylation increased fibril stability relative to the unmodified peptide. These findings show that phosphorylation within the tau fibril core promotes fibril registry and stability through water‐mediated, hydrogen‐bonded phosphoryl wires, which may be a structural signature for next‐generation pathological tau binders.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02
preprintOpen accessSenior authorCorrespondingThe phase separation of lipid bilayers, composed of mixtures of saturated and unsaturated lipids and cholesterol, is a topic of fundamental importance in membrane biophysics and cell biology. The formation of lipid domains, including liquid-disordered domains enriched in unsaturated lipids and liquid-ordered domains enriched in saturated lipids and cholesterol is believed to be essential to the function of many membrane proteins. Experiment, theory, and simulation have been used to develop a general understanding of the thermodynamic driving forces underlying phase separation in ternary and quaternary lipid mixtures. However, the kinetics of early events in lipid phase separation in the presence of transmembrane proteins remain relatively understudied. Using large-scale all-atom and coarse-grained simulations, we explore the kinetics and phase separation of ternary lipid mixtures of saturated lipid, unsaturated lipid, and cholesterol. Order parameters employed in the Cahn-Hilliard theory provide insight into the kinetics and mechanism of lipid phase separation. We observe three distinct time regimes in the phase separation process: a shorter time exponential phase followed by a power law phase followed by a longer time plateau phase. Comparison of lipid, protein and lipid-protein dynamics between all-atom and coarse-grained models identifies both quantitative and qualitative differences and similarities in the phase separation kinetics. Moreover, timescaling of dynamics of AA and CG simulation yields a similar kinetic mechanism of phase separation. The findings of this study elucidate fundamental aspects of membrane biophysics and the ongoing efforts to define the role of lipid rafts in the structure and function of cellular membrane.
Recent grants
Algorithms for the simulation of strong phase changes in complex molecular systems
NSF · $500k · 2011–2015
Algorithms for enhanced sampling and global optimization
NSF · $372k · 1999–2003
NIH · $1.1M · 2005
Complex role of solvation in protein structure and dynamics in micelles and membranes
NSF · $510k · 2014–2017
Probing the rules governing domain formation and protein partitioning in membrane
NSF · $510k · 2019–2024
Frequent coauthors
- 90 shared
D. Thirumalai
- 34 shared
Hiroshi Fujisaki
Nippon Medical School
- 32 shared
George A. Pantelopulos
National Institutes of Health
- 28 shared
Diane E. Sagnella
- 25 shared
Timothy A. Jackson
University of Kansas
- 25 shared
Manho Lim
Pusan National University
- 25 shared
Philip Anfinrud
National Institute of Diabetes and Digestive and Kidney Diseases
- 22 shared
Bogdan Tarus
Université Paris-Saclay
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