Research overview

The Sachs Lab is making innovative discoveries at the molecular scale. The work combines experimental biophysics and cell biology with sophisticated computational modeling using some of the world’s fastest supercomputers to explain how molecules malfunction in inflammatory diseases like arthritis, and neurodegenerative diseases like Parkinson’s. We use that new knowledge to develop cutting edge approaches to discover new therapeutic strategies, including small molecule drug discovery and protein engineering.

Lab website
 

Education

• BS, Mathematical Biochemistry, University of Michigan, 1996
• PhD, Biomedical Engineering, Johns Hopkins University, 2003
• NIH NRSA Postdoctoral Fellowship, Yale University, March 2004 - August 2006

Selected Publications

• Braun, A.R., Nathan Kochen, N., Yeun, S.L., Liao, E.E., Cornea, R.L., Thomas, D.D., and Sachs, J. N. (2023). Advancements in a FRET biosensor for live-cell fluorescence-lifetime high-throughput screening of alpha-synuclein. ASN Neuro, July 10. 
• Liao, E.E., Yang, M., Nathan Kochen, N., Vunnam, N., Braun, A.R., Ferguson, D.M., and Sachs, J.N. (2023) Proteasomal Stimulation by MK886 and Its Derivatives Can Rescue Tau-Induced Neurite Pathology. Molecular Neurobiology. July 10. 
• Nagamani,V., Young, M.C., Liao, E.E., Lo, C.H. ,Huber, E., Been, M. O. ,Thomas, D.D. and Sachs, J.N. (2023). Nimesulide, a COX-2 inhibitor, Sensitizes Pancreatic Cancer Cells to TRAIL-induced Apoptosis by Promoting DR5 Clustering. Cancer Biol Ther. Dec 31;24(1):2176692. 
• Nagamani, V., Been, M. O., Huber, E., Paulson, C. N., Szymonski, S.,  Hackel, B.J. and Sachs, J.N. (2023). Discovery of a Non-competitive TNFR1 Antagonist Affibody with Picomolar Monovalent Potency that Does not Affect TNFR2 Function. Mol Pharm. Mol Pharm. Mar 10. 
• Pandey A.K., Buchholz C.R., Kochen, N. N., Pomerantz, W.C.K., Braun, A.R., Sachs, JN.(2023) pH affects Can Dominate Chemical Shift Perturbations in 1H,15N-HSQC NMR Spectroscopy for Studies of Small Molecule/α-Synuclein Interactions. ACS Chem Neurosci. Feb 15;14(4):800-808.
• Nagamani, V., Yang, M,  Lo, C.H., Paulson, C.N., Fiers, W.D., Huber, E., Been, M. O., Ferguson, D. M. and Sachs, J. N. (2023). Zafirlukast is a promising scaffold for selectively inhibiting TNFR1 through alteration in receptor conformational states. ACS Bio & Med Chem Au, 3(3), 270–282.

2022

• Kochen, N. N., Vasandani, V., Seaney, D., Pandey, A. K., Walters, M. A., Braun, A. R., & Sachs, J. N. (2022). Threonine Cavities Are Targetable Motifs That Control Alpha-Synuclein Fibril Growth. ACS Chemical Neuroscience. 2022 Sep 7;13(17):2646-2657. 
• Vunnam, N., Hansen, S., Been, M. O., Lo, C. H., Pandey, A. K., Paulsen, C. N.,  and Wood, D. K. (2022). Fluorescence Lifetime Measurement of Prefibrillar Sickle Hemoglobin Oligomers as a Platform for Drug Discovery in Sickle Cell Disease. Biomacromolecules. Sep 12;23(9):3822-3830. 
• Ratnapriya S, Braun AR, Cervera Benet H, Carlson D, Ding S, Paulson CN, Mishra N, Sachs JN, Aldrich CC, Finzi A, Herschhorn, A. (2022) Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry. ACS Infect Dis. Oct 14;8(10):2045-2058. 

2021

• Lo, Chih Hung et al. “Fluorescence-Based TNFR1 Biosensor for Monitoring Receptor Structural and Conformational Dynamics and Discovery of Small Molecule Modulators.” Methods in molecular biology (Clifton, N.J.) vol. 2248 (2021): 121-137. 
• Braun, A. R., Liao, E. E., Horvath, M., Kalra, P., Acosta, K., Young, M. C., Kochen, N., Lo, C. H., Brown, R., Evans, M. D., Pomerantz, W. C. K., Rhoades, E., Luk, K., Cornea, R. L., Thomas, D. D., and Sachs, J. N. (2021). Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors. npj Parkinson's Disease, Vol. 7, 52. 

2020

• Lo, C. H., and Sachs, J.N. The role of wild-type tau in Alzheimer's disease and related tauopathies. Journal of life sciences (Westlake Village, Calif.) vol. 2,4 (2020): 1-17. 
• Vunnam, N., Szymonski, S., Hirsova, P., Gores, G. J., Sachs, J. N and Hackel, B. J. (2020). Noncompetitive Allosteric Antagonism of Death Receptor 5 by a Synthetic Affibody Ligand. Biochemistry, 59, 40, 3856–3868.
• Lo, C. H., Huber, E. C., Sachs, J. N. (2020). Conformational states of TNFR1 as a molecular switch for receptor function. Protein Science, 1-15.
• Braun, A. R. Liao, E. E., Horvath, M. Young, M. C., Lo, C. H., Brown, R., Evans, M. D., Luk, K., Thomas, D. D., Sachs, J. N. (2020). Potent inhibitors of toxic alpha-synuclein oligomers identified via cellular time-resolved FRET biosensor. Biorxiv, Posted January 09, 2020.
• West, A., Zoni, V., Teague Jr., W. E., Leonard, A. N., Vanni, S., Gawrisch, K., Tristram-Nagle, S., Sachs, J. N., Klauda, J. B. (2020). How Do Ethanolamine Plasmalogens Contribute to Order and Structure of Neurological Membranes? J. Phys. Chem. B 2020, 124, 5, 828-839.
• Lo CH, Pandey NK, Lim CK, Ding Z, Tao M, Thomas DD, Langen R, Sachs JN. Discovery of Small Molecule Inhibitors of Huntingtin Exon 1 Aggregation by FRET-Based High-Throughput Screening in Living Cells. ACS Chem Neurosci. 2020 Aug 5;11(15):2286-2295. doi: 10.1021/acschemneuro.0c00226. Epub 2020 Jul 7. PMID: 32568514.

2019

• Lo, C. H., Lim, C. K. W., Ding, Z., Wickramasinghe, S. P., Braun, A. R., Ashe, K. H., Rhoades, E., Thomas, D. D., Sachs, J. N. (2019). Targeting the ensemble of heterogeneous tau oligomers in cells: A novel small molecule screening platform for tauopathies. Alzheimer's and Dementia, 15(11), 1489-1502. 
• Lo, C. H., Schaaf, T. M., Grant, B. D., Lim, C. K. W., Bawaskar, P., Aldrich, C. C., Thomas, D. D., Sachs, J. N. (2019). Noncompetitive inhibitors of TNFR1 probe conformational activation states. Science signaling, 12(592), 5637. 

2017

• Vunnam, N., Lo, C.H., Grant, B.D., Thomas, D.D., Sachs, J.N. Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor–Receptor Interactions. J. Mol. Biol., September 2017. 
• Valley, C.C., Lewis, A.K., Sachs, J.N. Piecing it together: Unraveling the elusive structure-function relationship in single-pass membrane receptors. BBA-Biomembranes., September 2017.
• Vunnam, N., Campbell-Bezat, C.K., Lewis, A.K., Sachs, J.N. Death Receptor 5 Activation is Energetically Coupled to Opening of the Transmembrane Domain Dimer. Biophys. J, July 2017. 
• Romo, T.D., Lewis, A.K., Braun, A.R., Grossfield, A., Sachs, J.N. Minimal Nucleation State of α-Synuclein Is Stabilized by Dynamic Threonine–Water Networks. ACS Chem. Neurosci., July 2017. 
• Lo, C.H., Vunnam, N., Lewis, A.K., Chiu, T.L., Brummel, B.E., Schaaf, T.M., Grant, B.D., Bawaskar, P., Thomas, D.D., Sachs, J.N. An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors., SLAS Discovery., May 2017.
• Braun, A.R., Lacy, M.M., Ducas, V.C., Rhoades, E., Sachs, J.N. α-Synuclein’s Uniquely Long Amphipathic Helix Enhances its Membrane Binding and Remodeling Capacity. J. Membrane Biol., April 2017.
• Brummel, B.E., Braun, A.R., Sachs, J.N. Polyunsaturated chains in asymmetric lipids disorder raft mixtures and preferentially associate with α-Synuclein. BBA-Biomembranes., April 2017.
• Hennig, R., West, A., Debus, M., Saur, M., Markl, J., Sachs, J.N., Schneider, D. The IM30/Vipp1 C-terminus associates with the lipid bilayer and modulates membrane fusion. BBA-Bioenergetics, February 2017.

2016

• Lewis, A.K., Valley, C.C., Peery, S.L., Brummel, B.E., Braun, A.R., Karim, C.B., Sachs, J.N. Death Receptor 5 Networks Require Membrane Cholesterol for Proper Structure and Function. J. Mol. Biol., December 2016. 
• Lewis, A.K., Dunleavy, K.M., Senkow, T.L., Her, C., Horn, B.T., Jersett, M.A., Mahling, R., McCarthy, M.R., Perell, G.T., Valley, C.C., Karim, C.B., Gao, J., Pomerantz, W.C.K., Thomas, D.D., Cembran, A., Hinderliter, A., Sachs, J.N. Oxidation increases the strength of the methionine-aromatic interaction. Nature Chemical Biology., August 2016. 
• Romeo, C., Weber, M.C., Zarei, M., DeCicco, D., Chand, S.N., Lobo, A.D., Winter, J.M., Sawicki, J.A., Sachs, J.N., Meisner-Kober, N., Yeo, C.J., Vadigepalli, R., Tykocinski, M.L., Brody, J.R. HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells. Mol. Cancer Res., July 2016.
• West, A., Brummel, B.E., Braun, A.R., Rhoades, E., Sachs, J.N. Membrane remodeling and mechanics: Experiments and simulations of α-Synuclein. BBA-Biomembranes., March 2016.

2015

• Braun, A.R., Sachs, J.N. Alpha-synuclein reduces membrane surface tension and increases undulations in molecular dynamics simulations of small unilamellar vesicles. Biophys. J. Letters., April 2015.
• Shi, Z., Sachs, J.N., Rhoades E., and Baumgart, T. Biophysics of alpha-Synuclein induced membrane remodelling. Phys. Chem. Chem. Phys., Feb 2015.

2014

• Perlmutter, J.D., Popot, J.-L., and Sachs, J.N. Molecular Dynamics Simulations of a Membrane Protein/Amphipol Complex. J. Membr. Bio. June 2014.
• Tehei, M., Perlmutter, J.D., Giusti, F., Sachs, J.N., Zaccai, G., and Popot. J.-L. Thermal Fluctuations in Amphipol A8-35 Particles: A Neutron Scattering and Molecular Dynamics Study. J. Membr. Bio. Sep 2014.
• Braun, A.R. and Sachs, J.N. Determining structural and mechanical properties from molecular dynamics simulations of lipid vesicles. JCTC. Aug 2014.
• Braun, A.R., Lacy, M.M., Ducas, D.C., Rhoades, E., and Sachs, J.N. alpha-Synuclein induced membrane remodeling is driven by binding affinity, partition depth, and inter-leaflet order asymmetry. J. Am. Chem. Soc., June 2014, 136 (28), pp 9962–9972.
• Lewis, A.K., James, Z.M., McCaffrey, J.E., Braun, A.R., Karim, C.B., Thomas, D.D., and Sachs, J.N. Open and Closed Conformations of the Isolated Transmembrane Domain of Death Receptor 5 Support of a New Model of Activation. Biophys J. Volume 106, Issue 6, 18 March 2014, Pages L21–L24.

2013

• Braun, A.R., Sachs, J.N., and Nagle, J.F. Comparing Simulations of Lipid Bilayers to Scattering Data: The GROMOS 43A1-S3 Force Field. J Phys Chem B 2013 May 2;117(17):5065-5072

2012

• Valley, C.C., Cembran, A., Perlmutter, J.D., Lewis, A.K., Labello, N.P., Gao, J. and Sachs, J.N. The Methionine-aromatic motif plays a unique role in stabilizing protein structure. J Biol Chem. 2012 Oct 12;287(42):34979-91
• Lewis, A.K., Valley, C.C. and Sachs, J.N. TNFR1 Signaling is Associated with Backbone Conformational Changes of Receptor Dimers Consistent with Overactivation in the R92Q TRAPS Mutant. Biochemistry 2012 Jul 16;51(33):6545-6555 
• Valley, C.C., Lewis, A.K., Mudaliar, D.J., Perlmutter, J.D., Braun, A.R., Karim, C.B., Thomas, D.D, Brody, J.R. and Sachs, J.N. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces Death Receptor 5 networks that are highly organized. J Biol Chem. 2012 Jun 15;287(25):21265-78. Epub 2012 Apr 10.
• Braun, A.R., Sevcsik, E., Chin, P., Rhoades, E., Tristram-Nagle, S., and Sachs, J.N. α-Synuclein induces both positive mean curvature and negative Gaussian curvature in membranes. J Am Chem Soc. 2012 Feb 8; 134(5):2613-20.

2000-2011

• Valley, C.C., Perlmutter, J.D., Braun, A.R., and Sachs, J.N. NaCl interactions with phosphatidylcholine bilayers do not alter membrane structure, but induce long-range ordering of ions and water. J Membrane Biology. 2011 Nov; 244(1):35-42.
• Braun, A.R., Sachs, J.N. Extracting experimental measurables from molecular dynamics simulations of membranes. Annual Reports in Computational Chemistry, ARCC Vol 7, Chapter 6.
• Popot, J.L., ..., Sachs, J.N., ... et al. Amphipols From A to Z. Annual Review of Biophysics Volume: 40 Pages: 379-408.
• Perlmutter, J.D., Drasler W.J., Xie W., Gao J., Popot J.L., and Sachs J.N. All-atom and coarse-grained molecular dynamics simulations of a membrane protein stabilizing polymer. Langmuir. 2011 Sep 6;27(17):10523-37. Epub 2011 Aug 15.
• Perlmutter, J.D., Sachs, J.N. Inter-Leaflet Interaction and Asymmetry in Phase Separated Lipid Bilayers: Molecular Dynamics Simulations. J Am Chem Soc. 2011 May 4;133(17):6563-77.
• Braun, A.R., Brandt, E., Edholm, O., Nagle, J.F., and Sachs, J.N. Determination of Electron Density Profiles and Area from Simulations of Undulating Membranes. Biophys J. 2011 May 4;100(9):2112-20.
• Brandt, E., Braun, A.R., Sachs, J.N., Nagle, J.F., and Edholm, O. Interpretation of Fluctuation Spectra in Lipid Bilayer Simulations. Biophys J. 2011 May 4;100(9):2104-11.
• Denning E.J., Crozier P.S., Sachs J.N., and Woolf, T.B. From the gating charge response to pore domain movement: initial motions of Kv1.2 dynamics under physiological voltage changes. Mol Membr Biol. 2009 Dec;26(8):397-421.
• Perlmutter, JD., Sachs, JN. Inhibiting Lateral Domain Formation in Lipid Bilayers: Simulations of Alternative Steroid Headgroup Chemistries. J. Am. Chem. Soc. 2009 131:16362–16363.
• Perlmutter, JD., Sachs, JN. Experimental verification of lipid bilayer structure through multi-scale modeling. Biochim. Biophys. Acta, Biomembr. 2009 1788:2284-2990.
• Perlmutter, JD., Braun, AR, and Sachs, JN. Curvature Dynamics of alpha-Synuclein Familial Parkinson’s Disease Mutants: Molecular Simulations of the Micelle-and Bilayer-Bound Forms. J. Biol. Chem. 2009 284: 7177-7189.
• Kucerka, N., Perlmutter J., Pan J., Tristram-Nagle S., Katsaras J. and Sachs JN. The effect of cholesterol on short- and long-chain monounsaturated lipid bilayers as determined by molecular dynamics simulations and x-ray scattering. Biophys. J. 2008. 95:2792-2805.
• Kucerka, N., Nagle JF., Sachs, JN.., Feller S.E., Pencer J., Jackson A., and Katsaras J. Lipid area refinement based on a simultaneous analysis of neutron and x-ray scattering data and all-atom molecular dynamics simulations. Biophys. J. 2008. 95:2356-2367. 
• Kucerka, K., Pencer, J., Sachs, JN., Nagle, JF. and Katsaras J. Curvature effect on the structure of phospholipid bilayers. Langmuir. 23 (3): 1292-1299 JAN 30 2007.
• Sachs, JN., Engelman, DM. Introduction to the Membrane Protein Reviews: The Interplay of Structure, Dynamics, and Environment in Membrane Protein Function. Annu Rev Biochem. 2006.
• Chin C, Sachs JN and Engelman DM. Transmembrane homodimerization of receptor-like protein tyrosine phosphatases. FEBS Lett. 579(17), 3855-8 2005.
• Nanda H, Sachs JN, Petrache HI, Woolf TB. Environmental effects on glycophorin A folding and structure examined through molecular simulations. J. Chem. Theory and Comp. (3): 375-388 2005. 
• Sachs JN, Shen H, and Saltzman WM. Polymers for gene therapy in cancer: New approaches for specificity of expression. Gene Therapy 12 (12): 954-955 2005. 
• Sachs JN, Crozier PS and Woolf TB. Atomistic simulations of biologically realistic transmembrane potential gradients. J. Chem. Phys. 121 (22): 10847-10851 2004. 
• Sachs JN, Petrache HI, and Woolf TB. Changes in phosphatidylcholine headgroup tilt and water order induced by monovalent salt: molecular dynamics simulations. Biophys. J. 86; 3772-3782 2004.
• Sachs JN, Woolf, TB. Understanding the Hofmeister effect in interactions between chaotropic anions and lipid bilayers: Molecular dynamics simulations. J. Amer. Chem. Soc. 125 (29): 8742-8743 2003. 
• Sachs JN, Petrache HI, and Woolf TB. Interpretation of small angle X-ray measurements guided by molecular dynamics simulations of lipid bilayers. Chem. Phys. Lip. 126: 211-223 2003.
• Sachs JN, Petrache HI, Zuckerman DM, and Woolf, TB. Molecular dynamics simulations of ionic concentration gradients across model bilayers. J. Chem. Phys. 118 (4): 1957-1969 2003. 
• Petrache HI, Zuckerman DM, Sachs JN, Killian JA, Koeppe RE II and Woolf, TB. Hydrophobic matching mechanism investigated by molecular dynamics simulations. Langmuir 18 (4): 1340-1351 2002.
• Grossfield, A., Sachs, J., and Woolf, TB. Dipole lattice membrane model for protein calculations. Proteins 41:211-223 2000.