Mechanistic Insights into the Binding of Different Positron Emission Tomography Tracers to Chronic Traumatic Encephalopathy Tau Protofibrils.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, and it is neuropathologically defined as the accumulation of abnormally hyperphosphorylated tau (p-tau). Early detection of p-tau in the brain is of great value in the prevention and treatment of CTE. Previous experimental studies reported that positron emission tomography (PET) technique using several tau tracers are available for imaging certain neurodegenerative diseases. However, few studies have focused on the development of CTE tau tracers. In this work, we performed conventional molecular docking and molecular dynamics simulations to address the binding properties and mechanisms of PET tracers (18F-PM-PBB3, 18F-CBD-2115, 18F-PI-2620, 18F-RO-948, 18F-MK-6240, and 18F-flortaucipir) to CTE tau protofibrils. The results show that the hydrophobic cavity and the top of the concave structure of CTE tau protofibrils are the preferred binding sites for the six tracers, and 18F-PM-PBB3 has the most competitive binding affinity to CTE tau protofibrils. Further investigation into the binding patterns of the six tracers to the CTE tau protofibrils showed that 18F-CBD-2115 and 18F-PM-PBB3 have a high number of H-bonds and hydrophobic contacts with tau protofibrils, resulting in strong hydrogen bonding and hydrophobic interactions; 18F-flortaucipir/18F-PI-2620 and 18F-PI-2620/18F-RO-948 form more intense π-π and cation-π interactions with tau protofibrils, respectively. Subsequently, we conducted a detailed analysis of the binding mechanism of 18F-PM-PBB3 to CTE tau protofibrils. The benzothiazole ring of 18F-PM-PBB3 exhibits stronger π-π stacking and cation-π interactions with tau protofibrils than the pyridine ring and forms a more concentrated T-shaped π-π stacking pattern. This study contributes to understanding the binding mechanism of PET tracers to CTE tau protofibrils and provides new insights into the design of potential novel tracers.

[1]  Keith A. Johnson,et al.  Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players , 2022, European Journal of Nuclear Medicine and Molecular Imaging.

[2]  Qingwen Zhang,et al.  Mechanistic insight into the disruption of Tau R3-R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study. , 2022, Physical Chemistry, Chemical Physics - PCCP.

[3]  C. Olsen,et al.  Chronic Traumatic Encephalopathy in the Brains of Military Personnel. , 2022, The New England journal of medicine.

[4]  Yu Zou,et al.  Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study , 2021, Frontiers in Molecular Biosciences.

[5]  Kevin F. Bieniek,et al.  Authors' Response. , 2021, Journal of neuropathology and experimental neurology.

[6]  Guanghong Wei,et al.  Molecular mechanisms of resveratrol and EGCG in the inhibition of Aβ42 aggregation and disruption of Aβ42 protofibril: similarities and differences. , 2021, Physical chemistry chemical physics : PCCP.

[7]  Qingwen Zhang,et al.  Mechanisms of melatonin binding and destabilizing the protofilament and filament of tau R3-R4 domains revealed by molecular dynamics simulation. , 2021, Physical chemistry chemical physics : PCCP.

[8]  H. Ågren,et al.  Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils , 2021, ACS chemical neuroscience.

[9]  M. Jinzaki,et al.  Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies , 2021, Brain communications.

[10]  Jiehui Jiang,et al.  Parametric Estimation of Reference Signal Intensity for Semi-Quantification of Tau Deposition: A Flortaucipir and [18F]-APN-1607 Study , 2021, Frontiers in Neuroscience.

[11]  A. Nordberg,et al.  Cryptic Sites in Tau Fibrils Explain the Preferential Binding of the AV-1451 PET Tracer toward Alzheimer’s Tauopathy , 2021, ACS chemical neuroscience.

[12]  C. Chipot,et al.  Cation-π interactions and their functional roles in membrane proteins. , 2021, Journal of molecular biology.

[13]  R. Petersen,et al.  National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome , 2021, Neurology.

[14]  A. Drzezga,et al.  Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework , 2021, European Journal of Nuclear Medicine and Molecular Imaging.

[15]  W. Klunk,et al.  Radiosynthesis, In Vitro and In Vivo Evaluation of [18F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies. , 2021, ACS chemical neuroscience.

[16]  M. Higuchi,et al.  Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling , 2020, International journal of molecular sciences.

[17]  O. Hansson,et al.  Optimized regional analysis to detect longitudinal 18F‐RO‐948 tau PET change in early AD , 2020 .

[18]  B. Luan,et al.  Structure-based lead optimization of herbal medicine rutin for inhibiting SARS-CoV-2's main protease. , 2020, Physical chemistry chemical physics : PCCP.

[19]  Virginia M. Y. Lee,et al.  High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer’s and Non-Alzheimer’s Disease Tauopathies , 2020, Neuron.

[20]  Muhammad Naveed Iqbal Qureshi,et al.  18F-MK-6240 PET for early and late detection of neurofibrillary tangles. , 2020, Brain : a journal of neurology.

[21]  F. Jessen,et al.  Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy , 2020, JAMA neurology.

[22]  Y. Guan,et al.  Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism , 2020, Frontiers in Neuroscience.

[23]  Y. Guan,et al.  Tau PET Imaging with [18F]PM-PBB3 in Frontotemporal Dementia with MAPT Mutation. , 2020, Journal of Alzheimer's disease : JAD.

[24]  O. Hansson,et al.  Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders , 2020, JAMA neurology.

[25]  Ramesh Chandra,et al.  Understanding the binding affinity of noscapines with protease of SARS-CoV-2 for COVID-19 using MD simulations at different temperatures , 2020, Journal of biomolecular structure & dynamics.

[26]  Val J Lowe,et al.  Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes. , 2020, JAMA neurology.

[27]  Özgür A. Onur,et al.  Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury , 2020, European Journal of Nuclear Medicine and Molecular Imaging.

[28]  T. Yen,et al.  Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy , 2020, Molecules.

[29]  H. Ågren,et al.  Computational Insight into the Binding Profile of the Second-Generation PET Tracer PI2620 with Tau Fibrils. , 2020, ACS chemical neuroscience.

[30]  L. Grinberg,et al.  Tau Positron Emission Tomographic Findings in a Former US Football Player With Pathologically Confirmed Chronic Traumatic Encephalopathy. , 2020, JAMA neurology.

[31]  J. Seibyl,et al.  Tau PET imaging with 18F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study , 2019, The Journal of Nuclear Medicine.

[32]  B. Miller,et al.  Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy , 2019, NeuroImage: Clinical.

[33]  O. Hansson,et al.  Head-to-head comparison of tau positron emission tomography tracers [18F]flortaucipir and [18F]RO948 , 2019, European Journal of Nuclear Medicine and Molecular Imaging.

[34]  G. Kenttä,et al.  Canadian Centre for Mental Health and Sport (CCMHS) Position Statement: Principles of Mental Health in Competitive and High-Performance Sport , 2019, Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine.

[35]  M. Mintun,et al.  Tau Positron‐Emission Tomography in Former National Football League Players , 2019, The New England journal of medicine.

[36]  A. Murzin,et al.  Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules , 2019, Nature.

[37]  A. Nordberg,et al.  Tau PET imaging in neurodegenerative tauopathies—still a challenge , 2019, Molecular Psychiatry.

[38]  E. Chi,et al.  Computational Study of the Driving Forces and Dynamics of Curcumin Binding to Amyloid-β Protofibrils. , 2019, The journal of physical chemistry. B.

[39]  Hans Ågren,et al.  Mechanistic Insight into the Binding Profile of DCVJ and α-Synuclein Fibril Revealed by Multiscale Simulations. , 2018, ACS chemical neuroscience.

[40]  Stefano Moro,et al.  Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview , 2018, Front. Pharmacol..

[41]  N. Okamura,et al.  The development and validation of tau PET tracers: current status and future directions , 2018, Clinical and Translational Imaging.

[42]  H. Ågren,et al.  Different Positron Emission Tomography Tau Tracers Bind to Multiple Binding Sites on the Tau Fibril: Insight from Computational Modeling. , 2018, ACS chemical neuroscience.

[43]  Guanghong Wei,et al.  Orcein-Related Small Molecule O4 Destabilizes hIAPP Protofibrils by Interacting Mostly with the Amyloidogenic Core Region. , 2017, The journal of physical chemistry. B.

[44]  Victor L Villemagne Selective Tau Imaging: Der Stand der Dinge* , 2017, The Journal of Nuclear Medicine.

[45]  Christine M Baugh,et al.  Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football , 2017, JAMA.

[46]  Ruth Huey,et al.  Computational protein–ligand docking and virtual drug screening with the AutoDock suite , 2016, Nature Protocols.

[47]  Wayne A. Gordon,et al.  The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy , 2015, Acta Neuropathologica.

[48]  Keith A. Johnson,et al.  Validating novel tau positron emission tomography tracer [F‐18]‐AV‐1451 (T807) on postmortem brain tissue , 2015, Annals of neurology.

[49]  Berk Hess,et al.  GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers , 2015 .

[50]  Guanghong Wei,et al.  Atomic-level study of the effects of O4 molecules on the structural properties of protofibrillar Aβ trimer: β-sheet stabilization, salt bridge protection, and binding mechanism. , 2015, The journal of physical chemistry. B.

[51]  Rajendra Kumar,et al.  g_mmpbsa - A GROMACS Tool for High-Throughput MM-PBSA Calculations , 2014, J. Chem. Inf. Model..

[52]  Ann C. McKee,et al.  Clinical presentation of chronic traumatic encephalopathy , 2013, Neurology.

[53]  D. Dougherty The cation-π interaction. , 2013, Accounts of chemical research.

[54]  Tian Lu,et al.  Multiwfn: A multifunctional wavefunction analyzer , 2012, J. Comput. Chem..

[55]  Piotr Cieplak,et al.  The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building. , 2010, Physical chemistry chemical physics : PCCP.

[56]  C. David Sherrill,et al.  Potential energy curves for cation-pi interactions: off-axis configurations are also attractive. , 2009, The journal of physical chemistry. A.

[57]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[58]  Shawn T. Brown,et al.  Advances in methods and algorithms in a modern quantum chemistry program package. , 2006, Physical chemistry chemical physics : PCCP.

[59]  Paul J van Maaren,et al.  Thermodynamics of hydrogen bonding in hydrophilic and hydrophobic media. , 2006, The journal of physical chemistry. B.

[60]  Gerrit Groenhof,et al.  GROMACS: Fast, flexible, and free , 2005, J. Comput. Chem..

[61]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[62]  Ray Luo,et al.  Accelerated Poisson–Boltzmann calculations for static and dynamic systems , 2002, J. Comput. Chem..

[63]  Edward F. Valeev,et al.  Estimates of the Ab Initio Limit for π−π Interactions: The Benzene Dimer , 2002 .

[64]  Ehud Gazit,et al.  A possible role for π‐stacking in the self‐assembly of amyloid fibrils , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[65]  J. Gallivan,et al.  A Computational Study of Cation−π Interactions vs Salt Bridges in Aqueous Media: Implications for Protein Engineering , 2000 .

[66]  Berk Hess,et al.  LINCS: A linear constraint solver for molecular simulations , 1997, J. Comput. Chem..

[67]  D. A. Dougherty,et al.  The Cationminus signpi Interaction. , 1997, Chemical reviews.

[68]  Mark S. Gordon,et al.  General atomic and molecular electronic structure system , 1993, J. Comput. Chem..

[69]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[70]  P. Kollman,et al.  Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models , 1992 .

[71]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[72]  M. Parrinello,et al.  Polymorphic transitions in single crystals: A new molecular dynamics method , 1981 .

[73]  G. Small,et al.  Postmortem 3-D brain hemisphere cortical tau and amyloid-β pathology mapping and quantification as a validation method of neuropathology imaging. , 2013, Journal of Alzheimer's disease : JAD.