Unravelling the molecular basis of AM-6494 high potency at BACE1 in Alzheimer’s disease: an integrated dynamic interaction investigation

References

• Aldeghi, M., Bodkin, M. J., Knapp, S., & Biggin, P. C. (2017). Statistical analysis on the performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study. Journal of Chemical Information and Modeling, 57(9), 2203–2221. https://doi.org/https://doi.org/10.1021/acs.jcim.7b00347
   PubMed Web of Science ®Google Scholar
• Baker, J. L., Biais, N., & Tama, F. (2013). Steered molecular dynamics simulations of a type IV pilus probe initial stages of a force-induced conformational transition. PLoS Computational Biology, 9(4), e1003032. https://doi.org/https://doi.org/10.1371/journal.pcbi.1003032
   PubMed Web of Science ®Google Scholar
• Becke, A. D. (1993). Density functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics, 98(7), 5648–5652. https://doi.org/https://doi.org/10.1063/1.464913
   Web of Science ®Google Scholar
• Berendsen, H. J., Postma, J., van Gunsteren, W. F., DiNola, A., & Haak, J. R. (1984). Molecular dynamics with coupling to an external bath. The Journal of Chemical Physics, 81(8), 3684–3690. https://doi.org/https://doi.org/10.1063/1.448118
   Web of Science ®Google Scholar
• Bergonzo, C., & Cheatham, I. I T. (2015). Improved force field parameters lead to a better description of RNA structure. Journal of Chemical Theory and Computation, 11(9), 3969–3972. https://doi.org/https://doi.org/10.1021/acs.jctc.5b00444
   PubMed Web of Science ®Google Scholar
• Bhati, A. P., Wan, S., Wright, D. W., & Coveney, P. V. (2017). Rapid, accurate, precise, and reliable relative free energy prediction using ensemble based thermodynamic integration. Journal of Chemical Theory and Computation, 13(1), 210–222. https://doi.org/https://doi.org/10.1021/acs.jctc.6b00979
   PubMed Web of Science ®Google Scholar
• Burger, S. K., Schofield, J., & Ayers, P. W. (2013). Quantum mechanics/molecular mechanics restrained electrostatic potential fitting. The Journal of Physical Chemistry. B, 117(48), 14960–14966. https://doi.org/https://doi.org/10.1021/jp409568h
   PubMed Web of Science ®Google Scholar
• Cai, Y., Kurt Yilmaz, N., Myint, W., Ishima, R., & Schiffer, C. A. (2012). Differential flap dynamics in wild-type and a drug resistant variant of HIV-1 protease revealed by molecular dynamics and NMR relaxation. Journal of Chemical Theory and Computation, 8(10), 3452–3462. https://doi.org/https://doi.org/10.1021/ct300076y
   PubMed Web of Science ®Google Scholar
• Cascella, M., Micheletti, C., Rothlisberger, U., & Carloni, P. (2005). Evolutionarily conserved functional mechanics across pepsin-like and retroviral aspartic proteases. Journal of the American Chemical Society, 127(11), 3734–3742. https://doi.org/https://doi.org/10.1021/ja044608+
   PubMed Web of Science ®Google Scholar
• Chen, J., Wang, J., Pang, L., & Zhu, W. (2018). Inhibiting mechanism of small molecule towards the p53-MDM2 interaction: A molecular dynamic exploration. Chemical Biology & Drug Design, 92(4), 1763–1777. https://doi.org/https://doi.org/10.1111/cbdd.13345
   PubMed Web of Science ®Google Scholar
• Cummings, J., Lee, G., Ritter, A., & Zhong, K. (2018). Alzheimer’s disease drug development pipeline: 2018. Alzheimer's & Dementia (New York, N. Y.), 4, 195–214. https://doi.org/https://doi.org/10.1016/j.trci.2018.03.009
   PubMedGoogle Scholar
• Darden, T., York, D., & Pedersen, L. (1993). Particle mesh Ewald: An N⋅ log (N) method for Ewald sums in large systems. The Journal of Chemical Physics, 98(12), 10089–10092. https://doi.org/https://doi.org/10.1063/1.464397
   Web of Science ®Google Scholar
• Darden, T., York, D., & Pedersen, L. (1993). The effect of long-range electrostatic interactions in simulations of macromolecular crystals–a comparison of the Ewald and truncated list methods. The Journal of Chemical Physics, 99, 10089.
   Web of Science ®Google Scholar
• Das, B., & Yan, R. (2019). A close look at BACE1 inhibitors for Alzheimer's disease treatment. CNS Drugs, 33(3), 251–263. https://doi.org/https://doi.org/10.1007/s40263-019-00613-7
   PubMed Web of Science ®Google Scholar
• de Groot, B. L., Daura, X., Mark, A. E., & Grubmüller, H. (2001). Essential dynamics of reversible peptide folding: Memory-free conformational dynamics governed by internal hydrogen bonds. Journal of Molecular Biology, 309(1), 299–313. https://doi.org/https://doi.org/10.1006/jmbi.2001.4655
   PubMed Web of Science ®Google Scholar
• Deflorian, F., Perez-Benito, L., Lenselink, E. B., Congreve, M., van Vlijmen, H. W., Mason, J. S., Graaf, C., & Tresadern, G. (2020). Accurate prediction of GPCR ligand binding affinity with free energy perturbation. Journal of Chemical Information and Modeling, 60(11), 5563–5579. https://doi.org/https://doi.org/10.1021/acs.jcim.0c00449
   PubMed Web of Science ®Google Scholar
• dos Santos, P., Leide, C., Ozela, P. F., de Fatima de Brito Brito, M., Pinheiro, A. A., Padilha, E. C., Braga, F. S., Carlos, H., dos Santos, C. B. R., & Rosa, J. (2018). Alzheimer’s disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Current Medicinal Chemistry, 25(26), 3141–3159. https://doi.org/https://doi.org/10.2174/0929867323666161213101126
   PubMed Web of Science ®Google Scholar
• Efthymiou, A. G., & Goate, A. M. (2017). Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Molecular Neurodegeneration, 12(1), 43. https://doi.org/https://doi.org/10.1186/s13024-017-0184-x
   PubMedGoogle Scholar
• Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Petersson, G. A., Nakatsuji, H., Li, X., Caricato, M., Marenich, A. V., Bloino, J., Janesko, B. G., Gomperts, R., Mennucci, B., Hratchian, H. P., Ortiz, J. V., Izmaylov, A. F., … Fox, D. J. (2016). Gaussian 16 Rev. B.01. Wallingford, CT.
   Google Scholar
• Gedeon, P. C., Thomas, J. R., & Madura, J. D. (2015). Accelerated molecular dynamics and protein conformational change: A theoretical and practical guide using a membrane embedded model neurotransmitter transporter. Molecular modelling of proteins (pp. 253–287). Springer.
   Google Scholar
• Gorfe, A. A., & Caflisch, A. (2005). Functional plasticity in the substrate binding site of beta-secretase. Structure (London, England : 1993)), 13(10), 1487–1498. https://doi.org/https://doi.org/10.1016/j.str.2005.06.015
   PubMed Web of Science ®Google Scholar
• Grant, B. J., Rodrigues, A. P., ElSawy, K. M., McCammon, J. A., & Caves, L. S. (2006). Bio3d: An R package for the comparative analysis of protein structures. Bioinformatics (Oxford, England)), 22(21), 2695–2696. https://doi.org/https://doi.org/10.1093/bioinformatics/btl461
   PubMed Web of Science ®Google Scholar
• Hamelberg, D., de Oliveira, C. A. F., & McCammon, J. A. (2007). Sampling of slow diffusive conformational transitions with accelerated molecular dynamics. The Journal of Chemical Physics, 127(15), 155102. https://doi.org/https://doi.org/10.1063/1.2789432
   PubMed Web of Science ®Google Scholar
• Hamelberg, D., Mongan, J., & McCammon, J. A. (2004). Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules. The Journal of Chemical Physics, 120(24), 11919–11929. https://doi.org/https://doi.org/10.1063/1.1755656
   PubMed Web of Science ®Google Scholar
• Hampel, H., Vassar, R., De Strooper, B., Hardy, J., Willem, M., Singh, N., Zhou, J., Yan, R., Vanmechelen, E., De Vos, A., Nisticò, R., Corbo, M., Imbimbo, B. P., Streffer, J., Voytyuk, I., Timmers, M., Tahami Monfared, A. A., Irizarry, M., Albala, B., … Vergallo, A. (2020). The β-secretase BACE1 in Alzheimer’s disease. Biological Psychiatry https://doi.org/https://doi.org/10.1016/j.biopsych.2020.02.001
   Google Scholar
• Hehre, W. J., Ditchfield, R., & Pople, J. A. (1972). Self-consistent molecular orbital methods. XII. Further extensions of Gaussian—type basis sets for use in molecular orbital studies of organic molecules. The Journal of Chemical Physics, 56(5), 2257–2261. https://doi.org/https://doi.org/10.1063/1.1677527
   Web of Science ®Google Scholar
• Herrup, K. (2015). The case for rejecting the amyloid cascade hypothesis. Nature Neuroscience, 18(6), 794–799. https://doi.org/https://doi.org/10.1038/nn.4017
   PubMed Web of Science ®Google Scholar
• Hornak, V., Okur, A., Rizzo, R. C., & Simmerling, C. (2006). HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations. Proceedings of the National Academy of Sciences of the United States of America, 103(4), 915–920. https://doi.org/https://doi.org/10.1073/pnas.0508452103
   PubMed Web of Science ®Google Scholar
• Hosen, S. Z., Dash, R., Junaid, M., Mitra, S., & Absar, N. (2019). Identification and structural characterisation of deleterious non-synonymous single nucleotide polymorphisms in the human SKP2 gene. Computational Biology and Chemistry, 79, 127–136. https://doi.org/https://doi.org/10.1016/j.compbiolchem.2019.02.003
   PubMed Web of Science ®Google Scholar
• Hou, T., Wang, J., Li, Y., & Wang, W. (2011). Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. Journal of Chemical Information and Modeling, 51(1), 69–82. https://doi.org/https://doi.org/10.1021/ci100275a
   PubMed Web of Science ®Google Scholar
• Ichiye, T., & Karplus, M. (1991). Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations. Proteins: Structure, Function, and Genetics, 11(3), 205–217. https://doi.org/https://doi.org/10.1002/prot.340110305
   PubMed Web of Science ®Google Scholar
• Izaguirre, J. A., Catarello, D. P., Wozniak, J. M., & Skeel, R. D. (2001). Langevin stabilisation of molecular dynamics. The Journal of Chemical Physics, 114(5), 2090–2098. https://doi.org/https://doi.org/10.1063/1.1332996
   Web of Science ®Google Scholar
• Jannat, S., Balupuri, A., Ali, M. Y., Hong, S. S., Choi, C. W., Choi, Y.-H., Ku, J.-M., Kim, W. J., Leem, J. Y., Kim, J. E., Shrestha, A. C., Ham, H. N., Lee, K.-H., Kim, D. M., Kang, N. S., & Park, G. H. (2019). Inhibition of β-site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via a specific structure-activity relationship with a strong BBB permeability. Experimental & Molecular Medicine, 51(2), 1–18. https://doi.org/https://doi.org/10.1038/s12276-019-0205-7
   PubMedGoogle Scholar
• Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., & Klein, M. L. (1983). Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics, 79(2), 926–935. https://doi.org/https://doi.org/10.1063/1.445869
   Web of Science ®Google Scholar
• Keskin, A. O., Durmaz, N., Uncu, G., Erzurumluoglu, E., Yıldırım, Z., Tuncer, N., & Adapınar, D. Ö. (2019). Future treatment of Alzheimer disease. Geriatric Medicine and Gerontology. IntechOpen.
   Google Scholar
• Koelsch, G. (2017). BACE1 function and inhibition: Implications of intervention in the amyloid pathway of Alzheimer’s disease pathology. Molecules, 22(10), 1723. https://doi.org/https://doi.org/10.3390/molecules22101723
   PubMed Web of Science ®Google Scholar
• Kumalo, H. M., Bhakat, S., & Soliman, M. E. (2016). Investigation of flap flexibility of β-secretase using molecular dynamic simulations. Journal of Biomolecular Structure & Dynamics, 34(5), 1008–1019. https://doi.org/https://doi.org/10.1080/07391102.2015.1064831
   PubMed Web of Science ®Google Scholar
• Kumalo, H., & Soliman, M. E. (2016). A comparative molecular dynamics study on BACE1 and BACE2 flap flexibility. Journal of Receptor and Signal Transduction Research, 36(5), 505–514. https://doi.org/https://doi.org/10.3109/10799893.2015.1130058
   PubMed Web of Science ®Google Scholar
• Lee, C., Yang, W., & Parr, R. G. (1988). Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical Review B: Condensed Matter, 37(2), 785–789. https://doi.org/https://doi.org/10.1103/physrevb.37.785
   PubMed Web of Science ®Google Scholar
• Lenselink, E. B., Louvel, J., Forti, A. F., van Veldhoven, J. P. D., de Vries, H., Mulder-Krieger, T., McRobb, F. M., Negri, A., Goose, J., Abel, R., van Vlijmen, H. W. T., Wang, L., Harder, E., Sherman, W., IJzerman, A. P., & Beuming, T. (2016). Predicting binding affinities for GPCR ligands using free-energy perturbation. ACS Omega, 1(2), 293–304. https://doi.org/https://doi.org/10.1021/acsomega.6b00086
   PubMed Web of Science ®Google Scholar
• Lindorff-Larsen, K., Piana, S., Dror, R. O., & Shaw, D. E. (2011). How fast-folding proteins fold. Science (New York, N.Y.).), 334(6055), 517–520. https://doi.org/https://doi.org/10.1126/science.1208351
   PubMed Web of Science ®Google Scholar
• Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E., & Simmerling, C. (2015). ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. Journal of Chemical Theory and Computation, 11(8), 3696–3713. https://doi.org/https://doi.org/10.1021/acs.jctc.5b00255
   PubMed Web of Science ®Google Scholar
• Markwick, P. R., & McCammon, J. A. (2011). Studying functional dynamics in bio-molecules using accelerated molecular dynamics. Physical Chemistry Chemical Physics, 13(45), 20053–20065. https://doi.org/https://doi.org/10.1039/c1cp22100k
   PubMed Web of Science ®Google Scholar
• Merck, S. (2018). Merck announces discontinuation of APECS Study Evaluating Verubecestat (MK-8931) for the treatment of people with prodromal Alzheimer’s disease. Merck. https://www.merck.com/news/merck-announces-discontinuation-of-apecs-study-evaluating-verubecestat-mk-8931-for-the-treatment-of-people-with-prodromal-alzheimers-disease/ (Accessed September 25, 2020).
   Google Scholar
• Miller, I. I B., McGee, T. D., JrSwails, J. M., Homeyer, N., Gohlke, H., & Roitberg, A. E. (2012). MMPBSA.py: An efficient program for end-state free energy calculations. Journal of Chemical Theory and Computation, 8(9), 3314–3321. https://doi.org/https://doi.org/10.1021/ct300418h
   PubMed Web of Science ®Google Scholar
• Narang, S. S., Goyal, D., & Goyal, B. (2019). Molecular insights into the inhibitory mechanism of bi-functional bis-tryptoline triazole against β-secretase (BACE1) enzyme. Amino Acids, 51(10-12), 1593–1607. https://doi.org/https://doi.org/10.1007/s00726-019-02797-0
   PubMed Web of Science ®Google Scholar
• Neumann, U., Ufer, M., Jacobson, L. H., Rouzade‐Dominguez, M. ‐L., Huledal, G., Kolly, C., Lüönd, R. M., Machauer, R., Veenstra, S. J., Hurth, K., Rueeger, H., Tintelnot‐Blomley, M., Staufenbiel, M., Shimshek, D. R., Perrot, L., Frieauff, W., Dubost, V., Schiller, H., Vogg, B., … Lopez Lopez, C. (2018). The BACE‐1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Molecular Medicine, 10(11), e9316. https://doi.org/https://doi.org/10.15252/emmm.201809316
   Google Scholar
• Park, H., & Lee, S. (2003). Determination of the active site protonation state of beta-secretase from molecular dynamics simulation and docking experiment: implications for structure-based inhibitor design. Journal of the American Chemical Society, 125(52), 16416–16422. https://doi.org/https://doi.org/10.1021/ja0304493
   PubMed Web of Science ®Google Scholar
• Patel, S., Vuillard, L., Cleasby, A., Murray, C. W., & Yon, J. (2004). Apo and inhibitor complex structures of BACE (beta-secretase)). Journal of Molecular Biology, 343(2), 407–416. https://doi.org/https://doi.org/10.1016/j.jmb.2004.08.018
   PubMed Web of Science ®Google Scholar
• Pearlman, D. A., Case, D. A., Caldwell, J. W., Ross, W. S., Cheatham, I. I T., DeBolt, S., Ferguson, D., Seibel, G., & Kollman, P. (1995). AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Computer Physics Communications, 91(1-3), 1–41. https://doi.org/https://doi.org/10.1016/0010-4655(95)00041-D
   Web of Science ®Google Scholar
• Pettus, L. H., Bourbeau, M. P., Bradley, J., Bartberger, M. D., Chen, K., Hickman, D., Johnson, M., Liu, Q., Manning, J. R., Nanez, A., Siegmund, A. C., Wen, P. H., Whittington, D. A., Allen, J. R., & Wood, S. (2020). Discovery of AM-6494: A potent and orally efficacious β-Site amyloid precursor protein cleaving Enzyme 1 (BACE1) inhibitor with in vivo selectivity over BACE2. Journal of Medicinal Chemistry, 63(5), 2263–2281. https://doi.org/https://doi.org/10.1021/acs.jmedchem.9b01034
   PubMed Web of Science ®Google Scholar
• Pople, J. A., Gill, P. M., & Johnson, B. G. (1992). Kohn—Sham density-functional theory within a finite basis set. Chemical Physics Letters, 199(6), 557–560. https://doi.org/https://doi.org/10.1016/0009-2614(92)85009-Y
   Web of Science ®Google Scholar
• Reitz, C., Brayne, C., & Mayeux, R. (2011). Epidemiology of Alzheimer disease. Nature Reviews. Neurology, 7(3), 137–152. https://doi.org/https://doi.org/10.1038/nrneurol.2011.2
   PubMed Web of Science ®Google Scholar
• Rifai, E. A., van Dijk, M., Vermeulen, N. P., & Geerke, D. P. (2018). Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: Application to the D3R Grand Challenge 2. Journal of Computer-Aided Molecular Design, 32(1), 239–249. https://doi.org/https://doi.org/10.1007/s10822-017-0055-0
   PubMed Web of Science ®Google Scholar
• Roe, D. R., & Cheatham, I. I T. (2013). PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. Journal of Chemical Theory and Computation, 9(7), 3084–3095. https://doi.org/https://doi.org/10.1021/ct400341p
   PubMed Web of Science ®Google Scholar
• Ryckaert, J.-P., Ciccotti, G., & Berendsen, H. J. (1977). Numerical integration of the Cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. Journal of Computational Physics, 23(3), 327–341. https://doi.org/https://doi.org/10.1016/0021-9991(77)90098-5
   Web of Science ®Google Scholar
• Salvadores, N., Sanhueza, M., Manque, P., & Court, F. A. (2017). Axonal degeneration during aging and its functional role in neurodegenerative disorders. Frontiers in Neuroscience, 11, 451 https://doi.org/https://doi.org/10.3389/fnins.2017.00451
   PubMed Web of Science ®Google Scholar
• Saravanan, K., Sivanandam, M., Hunday, G., Mathiyalagan, L., & Kumaradhas, P. (2019). Investigation of intermolecular interactions and stability of verubecestat in the active site of BACE1: Development of first model from QM/MM-based charge density and MD analysis. Journal of Biomolecular Structure and Dynamics, 37(9), 2339–2354. https://doi.org/https://doi.org/10.1080/07391102.2018.1479661
   PubMed Web of Science ®Google Scholar
• Schrödinger (2019). Schrödinger Release 2019–3, Maestro.
   Google Scholar
• Scott, J. D., Li, S. W., Brunskill, A. P., Chen, X., Cox, K., Cumming, J. N., Forman, M., Gilbert, E. J., Hodgson, R. A., & Hyde, L. A. (2016). Discovery of the 3-imino-1, 2, 4-thiadiazinane 1, 1-dioxide derivative verubecestat (MK-8931)–A β-site amyloid precursor protein cleaving enzyme 1 inhibitor for the treatment of Alzheimer’s disease. ACS Publications.
   Google Scholar
• Shaw, D. E., Maragakis, P., Lindorff-Larsen, K., Piana, S., Dror, R. O., Eastwood, M. P., Bank, J. A., Jumper, J. M., Salmon, J. K., Shan, Y., & Wriggers, W. (2010). Atomic-level characterisation of the structural dynamics of proteins. Science (New York, N.Y.), 330(6002), 341–346. https://doi.org/https://doi.org/10.1126/science.1187409
   PubMed Web of Science ®Google Scholar
• Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T., & Nukina, N. (2008). Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Molecular and Cellular Biology, 28(11), 3663–3671. https://doi.org/https://doi.org/10.1128/MCB.02185-07
   PubMed Web of Science ®Google Scholar
• Sinha, S., & Wang, S. M. (2020). Classification of VUS and unclassified variants in BRCA1 BRCT repeats by molecular dynamics simulation. Computational and Structural Biotechnology Journal, 18, 723–736. https://doi.org/https://doi.org/10.1016/j.csbj.2020.03.013
   PubMed Web of Science ®Google Scholar
• Sprenger, K., Jaeger, V. W., & Pfaendtner, J. (2015). The general AMBER force field (GAFF) can accurately predict thermodynamic and transport properties of many ionic liquids. The Journal of Physical Chemistry. B, 119(18), 5882–5895. https://doi.org/https://doi.org/10.1021/acs.jpcb.5b00689
   PubMed Web of Science ®Google Scholar
• Thaisrivongs, D. A., Morris, W. J., Tan, L., Song, Z. J., Lyons, T. W., Waldman, J. H., Naber, J. R., Chen, W., Chen, L., Zhang, B., & Yang, J. (2018). A next generation synthesis of BACE1 inhibitor verubecestat (MK-8931). Organic Letters, 20(6), 1568–1571. https://doi.org/https://doi.org/10.1021/acs.orglett.8b00259
   PubMed Web of Science ®Google Scholar
• Wall, M. E., Rechtsteiner, A., & Rocha, L. M. (2003). Singular value decomposition and principal component analysis. In Daniel P. Berrar, Werner Dubitzky, and Martin Granzow (Eds.), A practical approach to microarray data analysis (pp. 91–109). Boston, MA: Springer.
   Google Scholar
• Xu, Y., Li, M-j., Greenblatt, H., Chen, W., Paz, A., Dym, O., Peleg, Y., Chen, T., Shen, X., He, J., Jiang, H., Silman, I., & Sussman, J. L. (2012). Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations. Acta Crystallographica. Section D: Biological Crystallography, 68(Pt 1), 13–25. https://doi.org/https://doi.org/10.1107/S0907444911047251
   PubMedGoogle Scholar
• Zoete, V., & Michielin, O. (2007). Comparison between computational alanine scanning and per-residue binding free energy decomposition for protein-protein association using MM-GBSA: application to the TCR-p-MHC complex. Proteins, 67(4), 1026–1047. https://doi.org/https://doi.org/10.1002/prot.21395
   PubMed Web of Science ®Google Scholar