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. 2002 Sep;83(3):1620–1630. doi: 10.1016/S0006-3495(02)73931-3

Efficient generation of feasible pathways for protein conformational transitions.

Moon K Kim 1, Robert L Jernigan 1, Gregory S Chirikjian 1
PMCID: PMC1302259  PMID: 12202386

Abstract

We develop a computationally efficient method to simulate the transition of a protein between two conformations. Our method is based on a coarse-grained elastic network model in which distances between spatially proximal amino acids are interpolated between the values specified by the two end conformations. The computational speed of this method depends strongly on the choice of cutoff distance used to define interactions as measured by the density of entries of the constant linking/contact matrix. To circumvent this problem we introduce the concept of using a cutoff based on a maximum number of nearest neighbors. This generates linking matrices that are both sparse and uniform, hence allowing for efficient computations that are independent of the arbitrariness of cutoff distance choices. Simulation results demonstrate that the method developed here reliably generates feasible intermediate conformations, because our method observes steric constraints and produces monotonic changes in virtual bond and torsion angles. Applications are readily made to large proteins, and we demonstrate our method on lactate dehydrogenase, citrate synthase, and lactoferrin. We also illustrate how this framework can be used to complement experimental techniques that partially observe protein motions.

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Selected References

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  1. Atilgan A. R., Durell S. R., Jernigan R. L., Demirel M. C., Keskin O., Bahar I. Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys J. 2001 Jan;80(1):505–515. doi: 10.1016/S0006-3495(01)76033-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bahar I., Atilgan A. R., Erman B. Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential. Fold Des. 1997;2(3):173–181. doi: 10.1016/S1359-0278(97)00024-2. [DOI] [PubMed] [Google Scholar]
  3. Bahar I., Erman B., Jernigan R. L., Atilgan A. R., Covell D. G. Collective motions in HIV-1 reverse transcriptase: examination of flexibility and enzyme function. J Mol Biol. 1999 Jan 22;285(3):1023–1037. doi: 10.1006/jmbi.1998.2371. [DOI] [PubMed] [Google Scholar]
  4. Bahar I., Jernigan R. L. Vibrational dynamics of transfer RNAs: comparison of the free and synthetase-bound forms. J Mol Biol. 1998 Sep 4;281(5):871–884. doi: 10.1006/jmbi.1998.1978. [DOI] [PubMed] [Google Scholar]
  5. Balbach J., Forge V., van Nuland N. A., Winder S. L., Hore P. J., Dobson C. M. Following protein folding in real time using NMR spectroscopy. Nat Struct Biol. 1995 Oct;2(10):865–870. doi: 10.1038/nsb1095-865. [DOI] [PubMed] [Google Scholar]
  6. Berman H. M., Westbrook J., Feng Z., Gilliland G., Bhat T. N., Weissig H., Shindyalov I. N., Bourne P. E. The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235–242. doi: 10.1093/nar/28.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Booth A. G. Visualizing protein conformational changes on a personal computer--alpha carbon pseudo bonding as a constraint for interpolation in internal coordinate space. J Mol Graph Model. 2001;19(6):481–486. doi: 10.1016/s1093-3263(00)00088-7. [DOI] [PubMed] [Google Scholar]
  8. Brooks B., Karplus M. Harmonic dynamics of proteins: normal modes and fluctuations in bovine pancreatic trypsin inhibitor. Proc Natl Acad Sci U S A. 1983 Nov;80(21):6571–6575. doi: 10.1073/pnas.80.21.6571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brooks B., Karplus M. Normal modes for specific motions of macromolecules: application to the hinge-bending mode of lysozyme. Proc Natl Acad Sci U S A. 1985 Aug;82(15):4995–4999. doi: 10.1073/pnas.82.15.4995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bustamante C., Macosko J. C., Wuite G. J. Grabbing the cat by the tail: manipulating molecules one by one. Nat Rev Mol Cell Biol. 2000 Nov;1(2):130–136. doi: 10.1038/35040072. [DOI] [PubMed] [Google Scholar]
  11. Dyson H. J., Wright P. E. Insights into protein folding from NMR. Annu Rev Phys Chem. 1996;47:369–395. doi: 10.1146/annurev.physchem.47.1.369. [DOI] [PubMed] [Google Scholar]
  12. Gerstein M., Krebs W. A database of macromolecular motions. Nucleic Acids Res. 1998 Sep 15;26(18):4280–4290. doi: 10.1093/nar/26.18.4280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jäskeläinen S., Verma C. S., Hubbard R. E., Linko P., Caves L. S. Conformational change in the activation of lipase: an analysis in terms of low-frequency normal modes. Protein Sci. 1998 Jun;7(6):1359–1367. doi: 10.1002/pro.5560070612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kleywegt G. J., Jones T. A. Phi/psi-chology: Ramachandran revisited. Structure. 1996 Dec 15;4(12):1395–1400. doi: 10.1016/s0969-2126(96)00147-5. [DOI] [PubMed] [Google Scholar]
  15. Kleywegt G. J., Jones T. A. Where freedom is given, liberties are taken. Structure. 1995 Jun 15;3(6):535–540. doi: 10.1016/s0969-2126(01)00187-3. [DOI] [PubMed] [Google Scholar]
  16. Tama F., Sanejouand Y. H. Conformational change of proteins arising from normal mode calculations. Protein Eng. 2001 Jan;14(1):1–6. doi: 10.1093/protein/14.1.1. [DOI] [PubMed] [Google Scholar]
  17. Tirion M. M., ben-Avraham D. Normal mode analysis of G-actin. J Mol Biol. 1993 Mar 5;230(1):186–195. doi: 10.1006/jmbi.1993.1135. [DOI] [PubMed] [Google Scholar]
  18. Vonrhein C., Schlauderer G. J., Schulz G. E. Movie of the structural changes during a catalytic cycle of nucleoside monophosphate kinases. Structure. 1995 May 15;3(5):483–490. doi: 10.1016/s0969-2126(01)00181-2. [DOI] [PubMed] [Google Scholar]
  19. Wu P., Brand L. Resonance energy transfer: methods and applications. Anal Biochem. 1994 Apr;218(1):1–13. doi: 10.1006/abio.1994.1134. [DOI] [PubMed] [Google Scholar]
  20. Xu Z., Horwich A. L., Sigler P. B. The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex. Nature. 1997 Aug 21;388(6644):741–750. doi: 10.1038/41944. [DOI] [PubMed] [Google Scholar]
  21. Xu Z., Sigler P. B. GroEL/GroES: structure and function of a two-stroke folding machine. J Struct Biol. 1998 Dec 15;124(2-3):129–141. doi: 10.1006/jsbi.1998.4060. [DOI] [PubMed] [Google Scholar]

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