Skip to main content

Advertisement

SpringerLink
Log in

A molecular dynamics study of Cyclophilin A free and in complex with the Ala-Pro dipeptide

  • Original Paper
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

Abstract

Six different molecular dynamics simulations of Cyclophilin A, three with the protein free in water and three with the Ala-Pro dipeptide bound to the protein, have been performed, and analysed with respect to structure and hydration of the active site. The water structure in the binding pocket of the free Cyclophilin A was found to mimic the experimentally obtained binding cis conformation of the dipeptide. Cyclophilin A is a peptidyl–prolyl cis–trans isomerase (PPIase), but the mechanism of the cis/trans isomerization is not exactly clear. This study was performed to understand better the binding between dipeptide and Cyclophilin A, but also two previously proposed isomerization mechanisms are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ackerson B, Rey O, Canon J, Krogstad P (1998) Cells with high Cyclophilin A content support replication of human immunodeficiency virus type 1 gag mutants with decreased ability to incorporate Cyclophilin A. J Virol 72(1):303–308

    Google Scholar 

  • Allen MP, Tildesley DJ (1987) Computer simulations of liquids. Oxford Science Publications, Oxford

    Google Scholar 

  • Berendsen HJC, Grigera JR, Straatsma TP (1987) The missing term in effective pair potentials. J Phys Chem 91:6269–6271

    Article  Google Scholar 

  • Braun W, Kallen J, Mikol V, Walkinshaw MD, Wüthrich K (1995) Three-dimensional structure and actions of immunosuppressants and their immunophilins. FASEB J 9(1):63–72

    Google Scholar 

  • Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217

    Article  Google Scholar 

  • Cardenas ME, Lim E, Heitman J (1995) Mutations that perturb Cyclophilin A ligand binding pocket confer cyclosporin a resistance in Saccharomyces cerevisiae. J Biol Chem 270(36):20997–21002

    Article  Google Scholar 

  • Clubb RT, Ferguson SB, Walsh CT, Wagner G (1994) Three-dimensional solution structure of Escherichia coli periplasmic cyclophilin. Biochemistry 33(10):2761–2772

    Article  Google Scholar 

  • Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an Nlog(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  ADS  Google Scholar 

  • Eisenmesser EZ, Bosco DA, Akke M, Kern D (2002) Enzyme dynamics during catalysis. Science 295(5559):1520–1523

    Article  ADS  Google Scholar 

  • Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX (1989) Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337(6206):476–478

    Article  ADS  Google Scholar 

  • Fischer S, Michnick S, Karplus M (1993) A mechanism for rotamase catalysis by the FK506 binding protein (fkbr). Biochemistry 32(50):13830–13837

    Article  Google Scholar 

  • Franke EK, Yuan HE, Luban J (1994) Specific incorporation of Cyclophilin A into hiv-1 virions. Nature 372(6504):359–362

    Article  ADS  Google Scholar 

  • Gamble TR, Vajdos FF, Yoo S, Worthylake DK, Houseweart M, Sundquist WI, Hill CP (1996) Crystal structure of human Cyclophilin A bound to the amino-terminal domain of hiv-1 capsid. Cell 87(7):1285–1294

    Article  Google Scholar 

  • Grathwohl C, Wüthrich K (1981) NMR studies of the rates of proline cis-trans isomerization in oligopeptides. Biopolymers 20(12):2623–2633

    Article  Google Scholar 

  • Göthel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55(3):423–436

    Article  Google Scholar 

  • Hennig L, Christner C, Kipping M, Schelbert B, Rücknagel KP, Grabley S, Küllertz G, Fischer G (1998) Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone. Biochemistry 37(17):5953–5960

    Article  Google Scholar 

  • Hoover WG (1985) Canonical dynamics: equilibrium phase-scape distribution. Phys Rev A 31(3):1695–1697

    Article  ADS  Google Scholar 

  • Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38

    Article  Google Scholar 

  • Hur S, Bruice TC (2002) The mechanism of cis–trans isomerization of prolyl peptides by cyclophilin. J Am Chem Soc 124(25):7303–7313

    Article  Google Scholar 

  • Ivery MT (2000) Immunophilins: switched on protein binding domains? Med Res Rev 20(6):452–484

    Article  Google Scholar 

  • Kallen J, Walkinshaw MD (1992) The x-ray structure of a tetrapeptide bound to the active site of human Cyclophilin A. FEBS Lett 300(3):286–290

    Article  Google Scholar 

  • Kallen J, Spitzfaden C, Zurini MG, Wider G, Widmer H, Wüthrich K, Walkinshaw MD (1991) Structure of human Cyclophilin and its binding site for Cyclosporin A determined by x-ray crystallography and NMR spectroscopy. Nature 353(6341):276–279

    Article  ADS  Google Scholar 

  • Kallen J, Mikol V, Taylor P, Walkinshaw MD (1998) X-ray structures and analysis of 11 cyclosporin derivatives complexed with Cyclophilin A. J Mol Biol 283(2):435–449

    Article  Google Scholar 

  • Ke H (1992) Similarities and differences between human Cyclophilin A and other beta-barrel structures. Structural refinement at 1.63 A resolution. J Mol Biol 228(2):539–550

    Article  Google Scholar 

  • Ke H, Zydowsky LD, Liu J, Walsh CT (1991) Crystal structure of recombinant human t-cell cyclophilin a at 2.5 A resolution. Proc Natl Acad Sci USA 88(21):9483–9487

    Article  ADS  Google Scholar 

  • Ke H, Mayrose D, Cao W (1993a) Crystal structure of cyclophilin a complexed with substrate ala-pro suggests a solvent-assisted mechanism of cis-trans isomerization. Proc Natl Acad Sci USA 90(8):3324–3328

    Article  ADS  Google Scholar 

  • Ke H, Zhao Y, Luo F, Weissman I, Friedman J (1993b) Crystal structure of murine cyclophilin c complexed with immunosuppressive drug cyclosporin a. Proc Natl Acad Sci USA 90(20):11850–11854

    Article  ADS  Google Scholar 

  • Ke H, Mayrose D, Belshaw PJ, Alberg DG, Schreiber SL, Chang ZY, Etzkorn FA, Ho S, Walsh CT (1994) Crystal structures of cyclophilin a complexed with cyclosporin a and n-methyl-4-[(E)-2-butenyl]-4,4-dimethylthreonine cyclosporin a. Structure 2(1):33–44

    Article  Google Scholar 

  • Konno M, Ito M, Hayano T, Takahashi N (1996) The substrate-binding site in escherichia coli cyclophilin a preferably recognizes a cis-proline isomer or a highly distorted form of the trans isomer. J Mol Biol 256(5):897–908

    Article  Google Scholar 

  • MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher III WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616

    Article  Google Scholar 

  • Mark P, Nilsson L (2001a) Structure and dynamics of the TIP3P, SPC, and SPC/È water models at 298 K. J Phys Chem A 105(43):9954–9960

    Article  Google Scholar 

  • Mark P, Nilsson L (2001b) Molecular dynamics simulations of the ala-pro dipeptide in water: conformational dynamics of trans and cis isomers using different water models. J Phys Chem B 105(33):8028–8035

    Article  Google Scholar 

  • Mark P, Nilsson L (2002a) Structure and dynamics of liquid water with different long-range interaction truncation and temperature control methods in molecular dynamics simulations. J Comput Chem 23(13):1211–1219

    Article  Google Scholar 

  • Mark P, Nilsson L (2002b) A molecular dynamics study of tryptophan in water. J Phys Chem B 106(36):9440–9445

    Article  Google Scholar 

  • Mikol V, Kallen J, Pflügl G, Walkinshaw MD (1993) X-ray structure of a monomeric Cyclophilin A–Cyclosporin A crystal complex at 2.1 A resolution. J Mol Biol 234(4):1119–1130

    Article  Google Scholar 

  • Mikol V, Kallen J, Walkinshaw MD (1994) X-ray structure of a Cyclophilin B/cyclosporin complex: comparison with Cyclophilin A and delineation of its calcineurin-binding domain. Proc Natl Acad Sci USA 91(11):5183–5186

    Article  ADS  Google Scholar 

  • Mikol V, Ma D, Carlow CK (1998) Crystal structure of the cyclophilin-like domain from the parasitic nematode brugia malayi. Protein Sci 7(6):1310–1316

    Google Scholar 

  • Nosé S (1984) A molecular dynamics method for simulations in the canonical ensemble. Mol Phys 52:255–268

    Article  ADS  Google Scholar 

  • Nosé S (1990) Constant-temperature molecular dynamics. J Phys Condens Matter 2:115–119

    Article  ADS  Google Scholar 

  • Orozco M, Tirado-Rives J, Jorgensen WL (1993) Mechanism for the rotamase activity of FK506 binding protein from molecular dynamics simulations. Biochemistry 32(47):12864–12874

    Article  Google Scholar 

  • Ottiger M, Zerbe O, Güntert P, Wüthrich K (1997) The nmr solution conformation of unligated human Cyclophilin A. J Mol Biol 272(1):64–81

    Article  Google Scholar 

  • Pflügl G, Kallen J, Schirmer T, Jansonius JN, Zurini MG, Walkinshaw MD (1993) X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. Nature 361(6407):91–94

    Article  ADS  Google Scholar 

  • Pflügl GM, Kallen J, Jansonius JN, Walkinshaw MD (1994) The molecular replacement solution and x-ray refinement to 2.8 A of a decameric complex of human cyclophilin a with the immunosuppressive drug cyclosporin a. J Mol Biol 244(4):385–409

    Article  Google Scholar 

  • Pliyev BK, Gurvits BY (1999) Peptidyl-prolyl cis-trans isomerases: structure and functions. Biochemistry (Mosc) 64(7):738–751

    Google Scholar 

  • Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    Article  ADS  Google Scholar 

  • Sayle R, Milner-White EJ (1995) RasMol: biomolecular graphics for all. Trends Biochem Sci 20:374–376

    Article  Google Scholar 

  • Scholz C, Schindler T. Dolinski K, Heitman J, Schmid FX (1997) Cyclophilin active site mutants have native prolyl isomerase activity with a protein substrate. FEBS Lett 414(1):69–73

    Article  Google Scholar 

  • Scholz C, Maier P, Dolinski K, Heitman J, Schmid FX (1999) R73A and H144Q mutants of the yeast mitochondrial cyclophilin cpr3 exhibit a low prolyl isomerase activity in both peptide and protein-folding assays. FEBS Lett 443(3):367–369

    Article  Google Scholar 

  • Sherry B, Zybarth G, Alfano M, Dubrovsky L, Mitchell R, Rich D, Ulrich P, Bucala R, Cerami A, Bukrinsky M (1998) Role of Cyclophilin A in the uptake of hiv-1 by macrophages and T lymphocytes. Proc Natl Acad Sci USA 95(4):1758–1763

    Article  ADS  Google Scholar 

  • Spitzfaden C, Weber HP, Braun W, Kallen J, Wider G, Widmer H, Walkinshaw MD, Wüthrich K (1992) Cyclosporin A-cyclophilin complex formation. A model based on x-ray and NMR data. FEBS Lett 300(3):291–300

    Article  Google Scholar 

  • Spitzfaden C, Braun W, Wider G, Widmer H, Wüthrich K (1994) Determination of the NMR solution structure of the Cyclophilin A-Cyclosporin A complex. J Biomol NMR 4(4):463–482

    Article  Google Scholar 

  • Takahashi N, Hayano T, Suzuki M (1989) Peptidyl-prolyl cis-trans isomerase is the Cyclosporin A-binding protein Cyclophilin. Nature 337(6206):473–475

    Article  ADS  Google Scholar 

  • Taylor P, Husi H, Kontopidis G, Walkinshaw MD (1997) Structures of cyclophilin-ligand complexes. Prog Biophys Mol Biol 67(2–3):155–181

    Article  Google Scholar 

  • Thali M, Bukovsky A, Kondo E, Rosenwirth B, Walsh CT, Sodroski J, Göttlinger HG (1994) Functional association of cyclophilin a with hiv-1 virions. Nature 372(6504):363–365

    Article  ADS  Google Scholar 

  • Theriault Y, Logan TM, Meadows R, Yu L, Olejniczak ET, Holzman TF, Simmer RL, Fesik SW (1993) Solution structure of the Cyclosporin A/Cyclophilin complex by NMR. Nature 361(6407):88–91

    Article  ADS  Google Scholar 

  • Yoo S, Myszka DG, Yeh C, McMurray M, Hill CP, Sundquist WI (1997) Molecular recognition in the hiv-1 capsid/cyclophilin a complex. J Mol Biol 269(5):780–795

    Article  Google Scholar 

  • van Gunsteren WF, Berendsen HJC (1990) Computer simulation of molecular dynamics: methodology, applications, and perspectives in chemistry. Angew Chem Int Ed Engl 29:992–1023

    Article  Google Scholar 

  • Zhao Y, Ke H (1996a) Crystal structure implies that cyclophilin predominantly catalyzes the trans to cis isomerization. Biochemistry 35(23):7356–7361

    Article  Google Scholar 

  • Zhao Y, Ke H (1996b) Mechanistic implication of crystal structures of the cyclophilin-dipeptide complexes. Biochemistry 35(23):7362–7368

    Article  Google Scholar 

  • Zhao Y, Chen Y, Schutkowski M, Fisher G, Ke H (1997) Cyclophilin A complexed with a fragment of hiv-1 gag protein: insight into hiv-1 infectious activity. Structure 5(1):139–146

    Article  Google Scholar 

  • Zydowsky LD, Etzkorn FA, Chang HY, Ferguson SB, Stolz LA, Ho SI, Walsh CT (1992) Active site mutants of human cyclophilin a separate peptidyl-prolyl isomerase activity from cyclosporin a binding and calcineurin inhibition. Protein Sci 1(9):1092–1099

    Article  Google Scholar 

Download references

Acknowledgments

We thank Dr. Jan Norberg for critical reading of the manuscript. This work was supported by the Magnus Bergvall Foundation, the Swedish Natural Science Research Council and the Swedish Research Council for Engineering Science.

Author information

Author notes

  1. Pekka Mark

    Present address: School of Biotechnology, The Department of Theoretical Chemistry, Royal Institute of Technology, AlbaNova University Center, 106 91, Stockholm, Sweden

Authors and Affiliations

  1. Department of Biosciences and Nutrition, Karolinska Institutet, 141 57, Huddinge, Sweden

    Pekka Mark & Lennart Nilsson

Authors
  1. Pekka Mark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lennart Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lennart Nilsson.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary data (PDF 161 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mark, P., Nilsson, L. A molecular dynamics study of Cyclophilin A free and in complex with the Ala-Pro dipeptide. Eur Biophys J 36, 213–224 (2007). https://doi.org/10.1007/s00249-006-0121-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-006-0121-3

Keywords

Search

Navigation