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. 1998 Feb;74(2 Pt 1):681–693. doi: 10.1016/S0006-3495(98)73994-3

Simulations of fatty acid-binding proteins suggest sites important for function. I. Stearic acid.

T B Woolf 1
PMCID: PMC1302550  PMID: 9533682

Abstract

Molecular dynamics simulations of two structurally similar fatty acid-binding proteins interacting with stearic acid are described. The calculations relate to recent ligand binding measurements and suggest similarities and differences between the two systems. Charged and neutral forms of the fatty acid were examined. The charged forms led to rapid trajectory divergence, whereas the protonated forms remained stable over the length of their 1-ns production trajectories. The two protein systems showed similar sets of total interaction energies with the ligand. However, the strengths of individual amino acids interacting with the ligand differ. Furthermore, covariance analysis of the ligand with both protein and water suggests that the stearic acid in the adipocyte fatty acid-binding protein is coupled more strongly to the water than to the protein. The stearic acid in the muscle fatty acid-binding protein is seen to be coupled differentially along the length of the chain to the protein. These differences could help to rationalize the stronger binding affinity for stearic acid in the human muscle fatty acid-binding protein. An importance scale, based on both covariance and interaction energy with the ligand, is proposed to identify residues that may be important for binding function.

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Selected References

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  1. Ajay, Murcko M. A. Computational methods to predict binding free energy in ligand-receptor complexes. J Med Chem. 1995 Dec 22;38(26):4953–4967. doi: 10.1021/jm00026a001. [DOI] [PubMed] [Google Scholar]
  2. Aqvist J., Medina C., Samuelsson J. E. A new method for predicting binding affinity in computer-aided drug design. Protein Eng. 1994 Mar;7(3):385–391. doi: 10.1093/protein/7.3.385. [DOI] [PubMed] [Google Scholar]
  3. Banaszak L., Winter N., Xu Z., Bernlohr D. A., Cowan S., Jones T. A. Lipid-binding proteins: a family of fatty acid and retinoid transport proteins. Adv Protein Chem. 1994;45:89–151. doi: 10.1016/s0065-3233(08)60639-7. [DOI] [PubMed] [Google Scholar]
  4. Brown M. L., Venable R. M., Pastor R. W. A method for characterizing transition concertedness from polymer dynamics computer simulations. Biopolymers. 1995 Jan;35(1):31–46. doi: 10.1002/bip.360350105. [DOI] [PubMed] [Google Scholar]
  5. Buelt M. K., Xu Z., Banaszak L. J., Bernlohr D. A. Structural and functional characterization of the phosphorylated adipocyte lipid-binding protein (pp15). Biochemistry. 1992 Apr 7;31(13):3493–3499. doi: 10.1021/bi00128a025. [DOI] [PubMed] [Google Scholar]
  6. Cistola D. P., Sacchettini J. C., Banaszak L. J., Walsh M. T., Gordon J. I. Fatty acid interactions with rat intestinal and liver fatty acid-binding proteins expressed in Escherichia coli. A comparative 13C NMR study. J Biol Chem. 1989 Feb 15;264(5):2700–2710. [PubMed] [Google Scholar]
  7. Clarage J. B., Romo T., Andrews B. K., Pettitt B. M., Phillips G. N., Jr A sampling problem in molecular dynamics simulations of macromolecules. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3288–3292. doi: 10.1073/pnas.92.8.3288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Herr F. M., Matarese V., Bernlohr D. A., Storch J. Surface lysine residues modulate the collisional transfer of fatty acid from adipocyte fatty acid binding protein to membranes. Biochemistry. 1995 Sep 19;34(37):11840–11845. doi: 10.1021/bi00037a023. [DOI] [PubMed] [Google Scholar]
  9. Hodsdon M. E., Cistola D. P. Discrete backbone disorder in the nuclear magnetic resonance structure of apo intestinal fatty acid-binding protein: implications for the mechanism of ligand entry. Biochemistry. 1997 Feb 11;36(6):1450–1460. doi: 10.1021/bi961890r. [DOI] [PubMed] [Google Scholar]
  10. Jakoby M. G., Miller K. R., Toner J. J., Bauman A., Cheng L., Li E., Cistola D. P. Ligand-protein electrostatic interactions govern the specificity of retinol- and fatty acid-binding proteins. Biochemistry. 1993 Jan 26;32(3):872–878. doi: 10.1021/bi00054a019. [DOI] [PubMed] [Google Scholar]
  11. LaLonde J. M., Bernlohr D. A., Banaszak L. J. The up-and-down beta-barrel proteins. FASEB J. 1994 Dec;8(15):1240–1247. doi: 10.1096/fasebj.8.15.8001736. [DOI] [PubMed] [Google Scholar]
  12. LaLonde J. M., Bernlohr D. A., Banaszak L. J. X-ray crystallographic structures of adipocyte lipid-binding protein complexed with palmitate and hexadecanesulfonic acid. Properties of cavity binding sites. Biochemistry. 1994 Apr 26;33(16):4885–4895. doi: 10.1021/bi00182a017. [DOI] [PubMed] [Google Scholar]
  13. Maatman R. G., van Moerkerk H. T., Nooren I. M., van Zoelen E. J., Veerkamp J. H. Expression of human liver fatty acid-binding protein in Escherichia coli and comparative analysis of its binding characteristics with muscle fatty acid-binding protein. Biochim Biophys Acta. 1994 Aug 25;1214(1):1–10. doi: 10.1016/0005-2760(94)90002-7. [DOI] [PubMed] [Google Scholar]
  14. Matarese V., Bernlohr D. A. Purification of murine adipocyte lipid-binding protein. Characterization as a fatty acid- and retinoic acid-binding protein. J Biol Chem. 1988 Oct 5;263(28):14544–14551. [PubMed] [Google Scholar]
  15. Miller K. R., Cistola D. P. Titration calorimetry as a binding assay for lipid-binding proteins. Mol Cell Biochem. 1993 Jun 9;123(1-2):29–37. doi: 10.1007/BF01076472. [DOI] [PubMed] [Google Scholar]
  16. Rich M. R., Evans J. S. Molecular dynamics simulations of adipocyte lipid-binding protein: effect of electrostatics and acyl chain unsaturation. Biochemistry. 1996 Feb 6;35(5):1506–1515. doi: 10.1021/bi951574x. [DOI] [PubMed] [Google Scholar]
  17. Richieri G. V., Anel A., Kleinfeld A. M. Interactions of long-chain fatty acids and albumin: determination of free fatty acid levels using the fluorescent probe ADIFAB. Biochemistry. 1993 Jul 27;32(29):7574–7580. doi: 10.1021/bi00080a032. [DOI] [PubMed] [Google Scholar]
  18. Richieri G. V., Ogata R. T., Kleinfeld A. M. A fluorescently labeled intestinal fatty acid binding protein. Interactions with fatty acids and its use in monitoring free fatty acids. J Biol Chem. 1992 Nov 25;267(33):23495–23501. [PubMed] [Google Scholar]
  19. Richieri G. V., Ogata R. T., Kleinfeld A. M. Equilibrium constants for the binding of fatty acids with fatty acid-binding proteins from adipocyte, intestine, heart, and liver measured with the fluorescent probe ADIFAB. J Biol Chem. 1994 Sep 30;269(39):23918–23930. [PubMed] [Google Scholar]
  20. Richieri G. V., Ogata R. T., Kleinfeld A. M. Kinetics of fatty acid interactions with fatty acid binding proteins from adipocyte, heart, and intestine. J Biol Chem. 1996 May 10;271(19):11291–11300. doi: 10.1074/jbc.271.19.11291. [DOI] [PubMed] [Google Scholar]
  21. Richieri G. V., Ogata R. T., Kleinfeld A. M. Thermodynamics of fatty acid binding to fatty acid-binding proteins and fatty acid partition between water and membranes measured using the fluorescent probe ADIFAB. J Biol Chem. 1995 Jun 23;270(25):15076–15084. doi: 10.1074/jbc.270.25.15076. [DOI] [PubMed] [Google Scholar]
  22. Sacchettini J. C., Gordon J. I. Rat intestinal fatty acid binding protein. A model system for analyzing the forces that can bind fatty acids to proteins. J Biol Chem. 1993 Sep 5;268(25):18399–18402. [PubMed] [Google Scholar]
  23. Venable R. M., Zhang Y., Hardy B. J., Pastor R. W. Molecular dynamics simulations of a lipid bilayer and of hexadecane: an investigation of membrane fluidity. Science. 1993 Oct 8;262(5131):223–226. doi: 10.1126/science.8211140. [DOI] [PubMed] [Google Scholar]
  24. Xu Z., Bernlohr D. A., Banaszak L. J. Crystal structure of recombinant murine adipocyte lipid-binding protein. Biochemistry. 1992 Apr 7;31(13):3484–3492. doi: 10.1021/bi00128a024. [DOI] [PubMed] [Google Scholar]
  25. Xu Z., Bernlohr D. A., Banaszak L. J. The adipocyte lipid-binding protein at 1.6-A resolution. Crystal structures of the apoprotein and with bound saturated and unsaturated fatty acids. J Biol Chem. 1993 Apr 15;268(11):7874–7884. [PubMed] [Google Scholar]
  26. Young A. C., Scapin G., Kromminga A., Patel S. B., Veerkamp J. H., Sacchettini J. C. Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids. Structure. 1994 Jun 15;2(6):523–534. doi: 10.1016/s0969-2126(00)00052-6. [DOI] [PubMed] [Google Scholar]
  27. Zanotti G., Feltre L., Spadon P. A possible route for the release of fatty acid from fatty acid-binding protein. Biochem J. 1994 Jul 15;301(Pt 2):459–463. doi: 10.1042/bj3010459. [DOI] [PMC free article] [PubMed] [Google Scholar]

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