Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-β protein
Fufeng LIU, Wenjie DU, Yan SUN, Jie ZHENG, Xiaoyan DONG
Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-β protein
The aggregation of amyloid β-protein (Aβ) is tightly linked to the pathogenesis of Alzheimer’s disease. Previous studies have found that three peptide inhibitors (i.e., KLVFF, VVIA, and LPFFD) can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. However, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area (MM/PBSA) analysis, we examined the effect of three peptide inhibitors (KLVFF, VVIA, and LPFFD) on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modification and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.
Alzheimer’s disease / amyloid β-protein / peptide inhibitors / protein-protein interaction / molecular dynamics simulation
[1] |
Mattson M P. Pathways towards and away from Alzheimer’s disease. Nature, 2004, 430(7000): 631–639
|
[2] |
Blennow K, de Leon M J, Zetterberg H. Alzheimer’s disease. Lancet, 2006, 368(9533): 387–403
|
[3] |
Selkoe D J. The molecular pathology of Alzheimer’s disease. Neuron, 1991, 6(4): 487–498
|
[4] |
Miller D L, Papayannopoulos I A, Styles J, Bobin S A, Lin Y Y, Biemann K, Iqbal K. Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Archives of Biochemistry and Biophysics, 1993, 301(1): 41–52
|
[5] |
Kang J, Lemaire H G, Unterbeck A, Salbaum J M, Masters C L, Grzeschik K H, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature, 1987, 325(6106): 733–736
|
[6] |
Mattson M P. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiological Reviews, 1997, 77: 1081–1132
|
[7] |
Li X, Mehler E. Simulation of molecular crowding effects on an Alzheimer’s α-amyloid peptide. Cell Biochemistry and Biophysics, 2006, 46(2): 123–141
|
[8] |
Jarrett J T, Berger E P, Lansbury P T J. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry, 1993, 32(18): 4693–4697
|
[9] |
Zhang Y, McLaughlin R, Goodyer C, LeBlanc A. Selective cytotoxicity of intracellular amyloid β-peptide(1-42) through p53 and Bax in cultured primary human neurons. Journal of Cell Biology, 2002, 156(3): 519–529
|
[10] |
Simona F, Tiana G, Broglia R A, Colombo G. Modeling the alpha-helix to beta-hairpin transition mechanism and the formation of oligomeric aggregates of the fibrillogenic peptide A beta(12-28): Insights from all-atom molecular dynamics simulations. Journal of Molecular Graphics & Modelling, 2004, 23(3): 263–273
|
[11] |
Mager P P. Molecular simulation of the amyloid β-peptide Aβ-(1-40) of Alzheimer’s disease. Molecular Simulation, 1998, 20(4): 201–222
|
[12] |
Anand P, Hansmann U H E. Internal and environmental effects on folding and dimerisation of Alzheimer’s β-amyloid peptide. Molecular Simulation, 2011, 37(06): 440–448
|
[13] |
Xu Y, Shen J, Luo X, Zhu W, Chen K, Ma J, Jiang H. Conformational transition of amyloid β-peptide. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(15): 5403–5407
|
[14] |
Yang C, Zhu X L, Li J Y, Shi R W. Exploration of the mechanism for LPFFD inhibiting the formation of β-sheet conformation of Aβ(1–42) in water. Journal of Molecular Modeling, 2010, 16(4): 813–821
|
[15] |
Naeem A, Fazili N. Defective protein folding and aggregation as the basis of neurodegenerative diseases: The darker aspect of proteins. Cell Biochemistry and Biophysics, 2011, 61(2): 237–250
|
[16] |
Yu X, Wang J, Yang J C, Wang Q, Cheng S Z D, Nussinov R, Zheng J. Atomic-scale simulations confirm that soluble β-sheet-rich peptide self-assemblies provide amyloid mimics presenting similar conformational properties. Biophysical Journal, 2010, 98(1): 27–36
|
[17] |
Hamley I W. The amyloid beta peptide: A chemist’s perspective. Role in Alzheimer’s and fibrillization. Chemical Reviews, 2012, 112(10): 5147–5192
|
[18] |
Wang Q M, Yu X, Li L Y, Zheng J. Inhibition of amyloid-beta aggregation in Alzheimer’s disease. Current Pharmaceutical Design, 2014, 20(8): 1223–1243
|
[19] |
Liu F F, Ji L, Dong X Y, Sun Y. Molecular insight into the inhibition effect of trehalose on the nucleation and elongation of amyloid beta-peptide oligomers. Journal of Physical Chemistry B, 2009, 113(32): 11320–11329
|
[20] |
Wang C, Yang A, Li X, Li D, Zhang M, Du H, Li C, Guo Y, Mao X, Dong M, Besenbacher F, Yang Y, Wang C. Observation of molecular inhibition and binding structures of amyloid peptides. Nanoscale, 2012, 4(6): 1895–1909
|
[21] |
Soto C, Sigurdsson E M, Morelli L, Kumar R A, Castano E M, Frangione B. β-Sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer’s therapy. Nature Medicine, 1998, 4(7): 822–826
|
[22] |
Findeis M A, Musso G M, Arico-Muendel C C, Benjamin H W, Hundal A M, Lee J J, Chin J, Kelley M, Wakefield J, Hayward N J, Molineaux S M. Modified-peptide inhibitors of amyloid β-peptide polymerization. Biochemistry, 1999, 38(21): 6791–6800
|
[23] |
Fradinger E A, Monien B H, Urbanc B, Lomakin A, Tan M, Li H, Spring S M, Condron M M, Cruz L, Xie C W, Benedek G B, Bitan G.C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(37): 14175–14180
|
[24] |
Tjernberg L O, Naslund J, Lindqvist F, Johansson J, Karlstrom A R, Thyberg J, Terenius L, Nordstedt C. Arrest of β-amyloid fibril formation by a pentapeptide ligand. Journal of Biological Chemistry, 1996, 271(15): 8545–8548
|
[25] |
Singh P, Maji S. Amyloid-like fibril formation by Tachykinin neuropeptides and its relevance to amyloid β-protein aggregation and toxicity. Cell Biochemistry and Biophysics, 2012, 64(1): 29–44
|
[26] |
Mager P. Backpropagation neural network analysis applied to β-sheet breakers used against Alzheimer’s amyloid aggregation. Molecular Simulation, 2002, 28(3): 239–247
|
[27] |
Viet M H, Ngo S T, Lam N S, Li M S. Inhibition of aggregation of amyloid peptides by beta-sheet breaker peptides and their binding affinity. Journal of Physical Chemistry B, 2011, 115(22): 7433–7446
|
[28] |
Liu R, Yuan B, Emadi S, Zameer A, Schulz P, McAllister C, Lyubchenko Y, Goud G, Sierks M R. Single chain variable fragments against β-amyloid (Aβ) can inhibit Aβ aggregation and prevent Aβ-induced neurotoxicity. Biochemistry, 2004, 43(22): 6959–6967
|
[29] |
Manoutcharian K, Acero G, Munguia M E, Becerril B, Massieu L, Govezensky T, Ortiz E, Marks J D, Cao C, Ugen K, Gevorkian G. Human single chain Fv antibodies and a complementarity determining region-derived peptide binding to amyloid-β 1-42. Neurobiology of Disease, 2004, 17(1): 114–121
|
[30] |
Cabaleiro-Lago C, Quinlan-Pluck F, Lynch I, Lindman S, Minogue A M, Thulin E, Walsh D M, Dawson K A, Linse S. Inhibition of amyloid β protein fibrillation by polymeric nanoparticles. Journal of the American Chemical Society, 2008, 130(46): 15437–15443
|
[31] |
Takahashi T, Mihara H. Peptide and protein mimetics inhibiting amyloid β-peptide aggregation. Accounts of Chemical Research, 2008, 41(10): 1309–1318
|
[32] |
Soto C, Kindy M S, Baumann M, Frangione B. Inhibition of Alzheimer’s amyloidosis by peptides that prevent β-sheet conformation. Biochemical and Biophysical Research Communications, 1996, 226(3): 672–680
|
[33] |
Li H Y, Monien B H, Lomakin A, Zemel R, Fradinger E A, Tan M A, Spring S M, Urbanc B, Xie C W, Benedek G B, Bitan G. Mechanistic investigation of the inhibition of A beta 42 assembly and neurotoxicity by A beta 42 C-terminal fragments. Biochemistry, 2010, 49(30): 6358–6364
|
[34] |
Dong X Y, Du W J, Liu F F. Molecular dynamics simulation and binding free energy calculation of the conformational transition of amyloid peptide 42 inhibited by peptide inhibitors. Acta Physico-Chimica Sinica, 2012, 28: 2735–2744
|
[35] |
Hou T J, Wang J M, Li Y Y, Wang W. 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, 2011, 51(1): 69–82
|
[36] |
Hou T J, Wang J M, Li Y Y, Wang W. Assessing the performance of the molecular mechanics/poisson boltzmann surface area and molecular mechanics/generalized born surface area methods. II. The accuracy of ranking poses generated from docking. Journal of Computational Chemistry, 2011, 32(5): 866–877
|
[37] |
Xu L, Sun H Y, Li Y Y, Wang J M, Hou T J. Assessing the performance of MM/PBSA and MM/GBSA methods. 3. The impact of force fields and ligand charge models. Journal of Physical Chemistry B, 2013, 117(28): 8408–8421
|
[38] |
Wang J M, Hou T J, Xu X J. Recent advances in free energy calculations with a combination of molecular mechanics and continuum models. Current Computer-aided Drug Design, 2006, 2(3): 287–306
|
[39] |
Crescenzi O, Tomaselli S, Guerrini R, Salvadori S, D’Ursi A M, Temussi P A, Picone D. Solution structure of the Alzheimer amyloid β-peptide (1-42) in an apolar microenvironment. European Journal of Biochemistry, 2002, 269(22): 5642–5648
|
[40] |
van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A E, Berendsen H J C. GROMACS: Fast, flexible, and free. Journal of Computational Chemistry, 2005, 26(16): 1701–1718
|
[41] |
van Gunsteren W F, Billeter S R, Eising A A, Hünenberger P H, Krüger P, Mark A E, Scott W R P, Tironi I G. Biomolecular Simulation: The GROMOS96 Manual and Userguide. Zürich, Switzerland, Groningen, Holland, 1996
|
[42] |
Berendsen H J C, Postma J P M, van Gunsteren W F, Hermans J. In: Intermolecular Forces. Pullman B, ed. Reidel: Dordecht, Holland, 1981
|
[43] |
Bahrami H, Zahedi M, Moosavi-Movahedi A, Azizian H, Amanlou M. Theoretical investigation of interaction of sorbitol molecules with alcohol dehydrogenase in aqueous solution using molecular dynamics simulation. Cell Biochemistry and Biophysics, 2011, 59(2): 79–88
|
[44] |
Bussi G, Donadio D, Parrinello M. Canonical sampling through velocity rescaling. Journal of Chemical Physics, 2007, 126(1): 014101
|
[45] |
Berendsen H J C, Postma J P M, Gunsteren W F V, DiNola A, Haak J R. Molecular dynamics with coupling to an external bath. Journal of Chemical Physics, 1984, 81(8): 3684–3690
|
[46] |
Hess B, Bekker H, Berendsen H J C, Fraaije J G E M. LINCS: A linear constraint solver for molecular simulations. Journal of Computational Chemistry, 1997, 18(12): 1463–1472
|
[47] |
Verlet L. Computer “experiments” on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Physical Review, 1967, 159(1): 98–103
|
[48] |
Darden T, York D, Pedersen L. Particle mesh ewald: An N-log(N) method for ewald sums in large systems. Journal of Chemical Physics, 1993, 98(12): 10089–10092
|
[49] |
Zhou X Y, Xi W H, Luo Y, Cao S Q, Wei G H. Interactions of a water-soluble fullerene derivative with amyloid-beta protofibrils: Dynamics, binding mechanism, and the resulting salt bridge disruption. Journal of Physical Chemistry B, 2014, 118(24): 6733–6741
|
[50] |
Zoete V, Meuwly M, Karplus M. Study of the insulin dimerization: Binding free energy calculations and per-residue free energy decomposition. Proteins. Structure, Function, and Bioinformatics, 2005, 61(1): 79–93
|
[51] |
Milev S, Gorfe A A, Karshikoff A, Clubb R T, Bosshard H R, Jelesarov I. Energetics of sequence-specific protein-DNA association: Conformational stability of the DNA binding domain of integrase Tn916 and its cognate DNA duplex. Biochemistry, 2003, 42(12): 3492–3502
|
[52] |
Lafont V, Schaefer M, Stote R H, Altschuh D, Dejaegere A. Protein-protein recognition and interaction hot spots in an antigen-antibody complex: Free energy decomposition identifies “efficient amino acids”. Proteins. Structure, Function, and Bioinformatics, 2007, 67(2): 418–434
|
[53] |
Yan C L, Kaoud T, Lee S B, Dalby K N, Ren P Y. Understanding the specificity of a docking interaction between JNK1 and the scaffolding protein JIP1. Journal of Physical Chemistry B, 2011, 115(6): 1491–1502
|
[54] |
Huang B, Liu F F, Dong X Y, Sun Y. Molecular mechanism of the affinity interactions between protein A and human immunoglobulin G1 revealed by molecular simulations. Journal of Physical Chemistry B, 2011, 115(14): 4168–4176
|
[55] |
Huang B, Liu F F, Dong X Y, Sun Y. Molecular mechanism of the effects of salt and pH on the affinity between protein A and human immunoglobulin G1 revealed by molecular simulations. Journal of Physical Chemistry B, 2012, 116(1): 424–433
|
[56] |
Zheng J, Yu X, Wang J D, Yang J C, Wang Q M. Molecular modeling of two distinct triangular oligomers in amyloid beta-protein. Journal of Physical Chemistry B, 2010, 114(1): 463–470
|
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