ABSTRACT
Cystatin C can inhibit cysteine proteases and performs important physiological functions in cells. This protein is involved in the formation of amyloid fibers, and usually found in patients with Alzheimer's diseases or Down syndromes. Experimental evidence indicates that the mutation of human cystatin C 66th position, named L66Q is more likely to form dimers, which self-assemble subsequently to form amyloid deposits. However, the details about how the L66Q forms amyloid deposits are not clear. Here we used MD simulations and revealed that the single-site mutation in the 68th position of chicken cystatin C will cause changes in structural characteristics. The I68Q mutant has a higher fibro genic tendency than the wt, and the I68Q mutant has a tendency to “open” compared to the wt. The Loop1 region of I68Q has greater flexibility, and are easier to form dimers through domain exchange than wt, followed by further forming amyloid fiber deposits. Our study results are consistent with previous experimental conclusions, and provide a new idea for the future research of similar proteins. Besides, our conclusions also afford a solid theoretical basis for conquering amyloid diseases caused by cystatin C from a structural perspective.
- Abrahamson, M. and Grubb, A., 1994. Increased body temperature accelerates aggregation of the Leu-68–>Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy. Proc Natl Acad Sci U S A 91, 4 (Feb 15), 1416-1420. DOI= http://dx.doi.org/10.1073/pnas.91.4.1416.Google ScholarCross Ref
- Bode, W., Engh, R., Musil, D., Thiele, U., Huber, R., Karshikov, A., Brzin, J., Kos, J., and Turk, V., 1988. The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. EMBO J 7, 8 (Aug), 2593-2599.Google ScholarCross Ref
- Darden, T., York, D., and 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. DOI= http://dx.doi.org/10.1063/1.464397.Google ScholarCross Ref
- Feller, S.E., Zhang, Y., Pastor, R.W., and Brooks, B.R., 1995. Constant pressure molecular dynamics simulation: The Langevin piston method. The Journal of chemical physics 103, 11, 4613-4621. DOI= http://dx.doi.org/10.1063/1.470648.Google ScholarCross Ref
- Grubb, A.O., 2000. Cystatin C–properties and use as diagnostic marker. Adv Clin Chem 35, 63-99. DOI= http://dx.doi.org/10.1016/s0065-2423(01)35015-1.Google ScholarCross Ref
- Humphrey, W., Dalke, A., and Schulten, K., 1996. VMD: Visual molecular dynamics. Journal of Molecular Graphics 14, 1, 33-38. DOI= http://dx.doi.org/10.1016/0263-7855(96)00018-5.Google ScholarCross Ref
- Ibragimova, G.T. and Wade, R.C., 1998. Importance of Explicit Salt Ions for Protein Stability in Molecular Dynamics Simulation. Biophysical Journal 74, 6, 2906-2911. DOI= http://dx.doi.org/10.1016/S0006-3495(98)77997-4.Google ScholarCross Ref
- Janowski, R., Kozak, M., Jankowska, E., Grzonka, Z., Grubb, A., Abrahamson, M., and Jaskolski, M., 2001. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat Struct Biol 8, 4 (Apr), 316-320. DOI= http://dx.doi.org/10.1038/86188.Google ScholarCross Ref
- Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., and Klein, M.L., 1983. Comparison of simple potential functions for simulating liquid water. The Journal of chemical physics 79, 2, 926-935. DOI= http://dx.doi.org/10.1063/1.445869.Google ScholarCross Ref
- Mackerell, A.D., Bashford, D., Bellott, M., Dunbrack, R.L., Evanseck, J.D., Field, M.J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph-Mccarthy, D., Kuchnir, L., Kuczera, K., Lau, F.T.K., Mattos, C., Michnick, S., Ngo, T., Nguyen, D.T., Prodhom, B., Reiher, W.E., Roux, B., Schlenkrich, M., Smith, J.C., Stote, R., Straub, J., Watanabe, M., Wiorkiewicz-Kuczera, J., Yin, D., and Karplus, M., 1998. All-atom empirical potential for molecular modeling and dynamics studies of proteins. Journal of Physical Chemistry B 102, 18 (Apr 30), 3586-3616. DOI= http://dx.doi.org/DOI 10.1021/jp973084f.Google ScholarCross Ref
- Mahoney, M. and Jorgensen, W., 2000. A five- site model for liquid water and the reproduction of the density anomaly by rigid, nonpolarizable potential functions. Journal Of Chemical Physics 112, 20, 8910-8922.Google ScholarCross Ref
- Martin, K. and Mccammon, J.A., 2002. Molecular dynamics simulations of biomolecules. Nature Structural Biology 9, 9, 646. DOI= http://dx.doi.org/10.1038/nsb0902-646.Google Scholar
- Martyna, G.J., Tobias, D.J., and Klein, M.L., 1994. Constant pressure molecular dynamics algorithms. The Journal of chemical physics 101, 5, 4177-4189. DOI= http://dx.doi.org/10.1063/1.467468.Google ScholarCross Ref
- Miyamoto, S. and Kollman, P.A., 1992. Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models. Journal of Computational Chemistry 13, 8, 952-962. DOI= http://dx.doi.org/10.1002/jcc.540130805.Google ScholarDigital Library
- Phillips, J.C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Skeel, R.D., Kale, L., and Schulten, K., 2005. Scalable molecular dynamics with NAMD. J Comput Chem 26, 16 (Dec), 1781-1802. DOI= http://dx.doi.org/10.1002/jcc.20289.Google ScholarCross Ref
- Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F.T., De beer, T.A p., Rempfer, C., Bordoli, L., Lepore, R., and Schwede, T., 2018. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Research 46, W1, W296-W303. DOI= http://dx.doi.org/10.1093/nar/gky427.Google ScholarCross Ref
Recommendations
Homology modeling and molecular dynamic simulation of UDP-N-acetylmuramoyl-l-alanine-d-glutamate ligase (MurD) from Mycobacterium tuberculosis H37Rv using in silico approach
Graphical abstractDisplay Omitted
AbstractThe present study aimed to identify the prospective inhibitors of MurD, a cytoplasmic enzyme that catalyzes the addition of d-glutamate to the UDP-N-acetylmuramoyl-l-alanine nucleotide precursor in Mycobacterium tuberculosis (MTB), ...
Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations
Abstract BackgroundThe SARS-CoV-2 main protease (Mpro) is an attractive target in the COVID-19 drug development process. It catalyzes the polyprotein's translation from viral RNA and specifies a particular cleavage site. Due to the ...
Graphical abstractDisplay Omitted
Highlights- Molecule 3h interacted with catalytic dyad residues Cys145 and His41 of SARS-CoV-2 main protease.
Coarse-Grained Molecular Dynamics Simulation of Sulerythrin and LARFH for Producing Protein Nanofibers
ICBBB '18: Proceedings of the 2018 8th International Conference on Bioscience, Biochemistry and BioinformaticsArtificial creation of fibers utilizing proteins has been a target of bionanotechnology. Yagi et al. succeeded in designing artificial protein fibers using two types of proteins: LARFH and sulerythrin. Binding interfaces were designed for sulerythrin ...
Comments