About

Robert Guy Griffin is the Arthur Amos Noyes Professor of Chemistry at MIT. His research group is dedicated to the development of new magnetic resonance techniques to study molecular structure and dynamics. His work includes designing experiments to measure 13C-13C and 13C-15N dipolar couplings, performing spectral assignments, and measuring internuclear distances and torsion angles in solids using magic angle spinning (MAS) NMR spectra. This information is used to determine the molecular structures of amyloid and membrane peptides and proteins. In addition, Griffin's research involves developing high field dynamic nuclear polarization (DNP)/NMR experiments to obtain large nuclear spin polarizations and increased NMR signal intensities, enabling new applications. His team also performs CW and pulsed EPR experiments at 140 GHz to achieve higher resolution and easier interpretation of spectral lineshapes. They investigate dynamic processes in solids through analysis of 2H NMR powder patterns, deriving details about the rates and mechanisms of motion. The second major focus of his research is applying these magnetic resonance techniques to chemical, biophysical, and physical problems. His group employs MAS NMR to investigate the structure of large enzyme/inhibitor complexes, membrane proteins, and amyloid peptides and proteins. They have addressed structural questions by measuring chemical shifts and dipolar couplings between homonuclear and heteronuclear spin pairs. Notably, Griffin's team has performed NMR on photochemical intermediates of bacteriorhodopsin to study proton pumping mechanisms and the optical spectrum of retinal. They have also determined the initial structures of peptides in amyloid fibrils, such as an 11-mer from transthyretin, using high-resolution solid state NMR, which is essential for molecules that do not diffract or are insoluble.

Research topics

• Chemistry
• Nuclear magnetic resonance
• Photochemistry
• Organic chemistry
• Physical chemistry
• Atomic physics
• Chromatography
• Materials science
• Quantum mechanics
• Inorganic chemistry
• Physics

Selected publications

• BPS2026 – Aducanumab binding to Aβ1–42 fibrils alters dynamics of the N-terminal tail while preserving the fibril core

  Biophysical Journal · 2026-02-01

  articleSenior author
  PublisherDOI

• Atomic Structure of GNNQQNY Nanocrystals: A Validated Approach for Polymorphic Amyloids

  The Journal of Physical Chemistry Letters · 2025-12-15

  articleSenior authorCorresponding

  Magic angle spinning (MAS) nuclear magnetic resonance (NMR) is a powerful tool for determining the structures of complex biological systems like amyloid fibrils, which are often challenging to study due to polymorphism. However, traditional MAS NMR techniques are often limited by low signal-to-noise ratios (SNR) for long-range distances and by spectral overlap in degenerate systems. Here we establish an approach to address these challenges using the amyloid heptapeptide GNNQQNY, an ideal model for studying polymorphism due to its ability to assemble into either crystals or fibrils depending on preparation conditions. By employing specific 13C,15N-labeling to resolve spectral degeneracy associated with three asparagine and two glutamine residues, we obtained numerous high-precision distance restraints using frequency-selective rotational echo double resonance (FSR) and z-filtered transfer echo double resonance (ZF-TEDOR) experiments. These restraints enabled us to calculate the high-resolution MAS NMR structure of GNNQQNY nanocrystals, which closely matches the known X-ray crystal structure, thus validating our approach. Anticipating severe spectral degeneracies in studying polymorphic fibrils, we also introduce a novel FSR-RFDR pulse sequence which effectively deconvolves overlapped resonances, enabling precise distance measurements even in complex spectra. Our validated method, which includes specific labeling and the FSR-RFDR sequence, establishes a robust pipeline for future structural studies of heterogeneous amyloid fibrils, advancing our understanding of polymorphism at the atomic level.

  PublisherDOI

• Aducanumab Binding to Aβ1-42 Fibrils Alters Dynamics of the N-Terminal Tail While Preserving the Fibril Core

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-03

  preprintOpen accessSenior authorCorresponding

  Abstract Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated Aβ via the N-terminal region. Yet, the molecular details of how the antibody engages Aβ 1-42 fibrils remain unresolved. Using magic-angle spinning nuclear magnetic resonance, we show that binding of aducanumab preserves the overall architecture of the Aβ 1-42 fibril core while inducing significant structural and dynamic perturbations in the N-terminal region. Antibody binding markedly reduces flexibility in this domain, with the appearance of sidechain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These sidechains—previously observed only in scalar-coupling spectra of the unbound state—indicate rigidification of residues that were dynamic. The interaction extends to S8 and Y10, indicating broader fibril engagement than the minimal epitope (residues 3–7) defined in fragment-based studies. Perturbations in the C-terminal segment (G37–A42) are consistent with its spatial proximity to the antibody-bound N-termini of neighboring monomers. Cryo-TEM images reveal fibrils bundling in the presence of aducanumab, consistent with lateral association via antibody cross-linking, supporting a model where surface coating and steric hindrance suppress secondary nucleation. This mode of action restricts monomer access to catalytic sites on fibril surface, resulting in partial inhibition (∼three-fold reduction) of secondary nucleation. The effect depends on high avidity and relatively high stoichiometry, but is ultimately limited by antibody size relative to N-terminal spacing along the fibril. These findings provide atomic-level insights into aducanumab’s binding mode and supply a structural framework for understanding antibody-mediated fibril recognition and for guiding next-generation therapies targeting Aβ aggregates in Alzheimer’s disease. Significance Statement Understanding how therapeutic antibodies interact with amyloid-β (Aβ) fibrils is crucial for developing effective Alzheimer’s disease treatments. Magic angle spinning NMR provides atomic-level insights into the binding of aducanumab to mature Aβ 1-42 fibrils. Aducanumab binding preserves the fibril’s core structure but slows the dynamics of the N-terminal domain of Aβ. This interaction, which spans D1 to S8 and extends to Y10 on the fibril surface, is consistent with a mechanism in which N-terminal binding by the antibody interferes with aggregation steps like secondary nucleation. These findings detail how aducanumab engages its target fibril and provides insights relevant to other clinically approved antibodies and next-generation therapies that recognize the Aβ N-terminal region.

  PublisherOA PDFDOI

• Diamond rotors for high magic angle spinning frequencies

  Journal of Magnetic Resonance · 2025-05-26 · 1 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Diamond Rotors 2.0

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• Aducanumab binding to Aβ _1-42 fibrils alters dynamics of the N-terminal tail while preserving the fibril core

  Proceedings of the National Academy of Sciences · 2025-12-22 · 2 citations

  articleOpen accessSenior authorCorresponding

  Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated Aβ via the N-terminal region. Yet, the molecular details of how the antibody engages Aβ 1-42 fibrils remain unresolved. Using magic-angle spinning NMR, we show that binding of aducanumab preserves the overall architecture of the Aβ 1-42 fibril core while inducing significant structural and dynamic perturbations in the N-terminal region. Antibody binding markedly reduces flexibility in this domain, with the appearance of side-chain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These side chains—previously observed in scalar-coupling spectra of the unbound state—indicate rigidification of residues that were dynamic. The interaction extends to S8 and Y10, indicating broader fibril engagement than the minimal epitope (residues 3 to 7) defined in fragment-based studies. Perturbations in the C-terminal segment (G37–A42) are consistent with its spatial proximity to the antibody-bound N termini of neighboring monomers. Cryo-TEM images reveal fibrils bundling in the presence of aducanumab, consistent with lateral association via antibody cross-linking, supporting a model where surface coating and steric hindrance suppress secondary nucleation. This mode of action restricts monomer access to catalytic sites on the fibril surface, resulting in partial inhibition (~threefold reduction) of secondary nucleation. The effect depends on high avidity and relatively high stoichiometry but is ultimately limited by antibody size relative to N-terminal spacing along the fibril. These findings provide atomic-level insights into aducanumab’s binding mode and supply a structural framework for understanding antibody-mediated fibril recognition and for guiding next-generation therapies targeting Aβ aggregates in Alzheimer’s disease.

  PublisherDOI

• Diboron-Incorporated Indenofluorene: Isolation of Crystalline Neutral and Reduced States of 6,12-Diboraindeno[1,2-<i>b</i>]fluorene

  Journal of the American Chemical Society · 2025-05-21 · 13 citations

  articleOpen accessCorresponding

  The synthesis and redox transformations of 6,12-diboraindeno[1,2-b]fluorene (DBIF)─a pentacyclic π-system with diboron incorporation─are reported. In notable contrast to the all-hydrocarbon indenofluorenes, a ligand coordination and reduction strategy allows tuning of the electronic structure across four redox states. Accordingly, we introduce an 18π e– neutral DBIF, a 20π e– diradical, a 21π e– radical anion, and a 22π e– dianion, all of which have been isolated and structurally authenticated. The diradicals exhibit diradical character of up to 77% and possess open-shell singlet ground states with thermally accessible triplet states.

  PublisherOA PDFDOI

• Exploring the mechanisms of transverse relaxation of copper(II)-phthalocyanine spin qubits

  ArXiv.org · 2025-11-05 · 1 citations

  preprintOpen access

  Molecular spin qubits are promising candidates for quantum technologies, but their performance is limited by decoherence arising from diverse mechanisms. The complexity of the environment makes it challenging to identify the main source of noise and target it for mitigation. Here we present a systematic experimental and theoretical framework for analyzing the mechanisms of transverse relaxation in copper(II) phthalocyanine (CuPc) diluted into diamagnetic phthalocyanine hosts. Using pulsed EPR spectroscopy together with first-principles cluster correlation expansion simulations, we quantitatively separate the contributions from hyperfine-coupled nuclear spins, spin--lattice relaxation, and electron--electron dipolar interactions. Our detailed modeling shows that both strongly and weakly coupled nuclei contribute negligibly to $T_2$, while longitudinal dipolar interactions with electronic spins, through instantaneous and spectral diffusion, constitute the main decoherence channel even at moderate spin densities. This conclusion is validated by direct comparison between simulated spin-echo dynamics and experimental data. By providing a robust modeling and experimental approach, our work identifies favorable values of the electron spin density for quantum applications, and provides a transferable methodology for predicting ensemble coherence times. These insights will guide the design and optimization of molecular spin qubits for scalable quantum devices.

  PublisherOA PDFDOI

• Homonuclear J-Couplings and Heteronuclear Structural Constraints

  SSRN Electronic Journal · 2024-01-01

  preprintOpen accessSenior author
  PublisherDOI

• Dipolar Recoupling in Rotating Solids

  Chemical Reviews · 2024-11-06 · 24 citations

  reviewOpen accessSenior authorCorresponding

  Magic angle spinning (MAS) nuclear magnetic resonance (NMR) has evolved significantly over the past three decades and established itself as a vital tool for the structural analysis of biological macromolecules and materials. This review delves into the development and application of dipolar recoupling techniques in MAS NMR, which are crucial for obtaining detailed structural and dynamic information. We discuss a variety of homonuclear and heteronuclear recoupling methods which are essential for measuring spatial restraints and explain in detail the spin dynamics that these sequences generate. We also explore recent developments in high spinning frequency MAS, proton detection, and dynamic nuclear polarization, underscoring their importance in advancing biomolecular NMR. Our aim is to provide a comprehensive account of contemporary dipolar recoupling methods, their principles, and their application to structural biology and materials, highlighting significant contributions to the field and emerging techniques that enhance resolution and sensitivity in MAS NMR spectroscopy.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM023403

  NIH · $2.3M · 2004

• NIH Grant R01EB003151

  NIH · $6.5M · 2017

• Solid State NMR Studies of Amyloid Proteins

  NIH · $3.1M · 2017–2022

• NIH Grant S10RR027895

  NIH · $300k · 2011

• NIH Grant R01GM025505

  NIH · $2.4M · 1996

Frequent coauthors

• Judith Herzfeld

  Brandeis University

  204 shared

• Richard J. Temkin

  186 shared

• Vladimir K. Michaelis

  78 shared

• Johan Lugtenburg

  Leiden University

  75 shared

• Sudheer Jawla

  58 shared

• Christopher P. Jaroniec

  The Ohio State University

  53 shared

• Björn Corzilius

  Leibniz Institute for Catalysis

  48 shared

• Marina Bennati

  University of Göttingen

  48 shared

Education

• Ph.D., Chemistry

  Washington University in Saint Louis

  1969