Advertisement

Conformational space of clindamycin studied by ab initio and full-atom molecular dynamics

  • Katarzyna Kulczycka-Mierzejewska
  • Joanna Trylska
  • Joanna SadlejEmail author
Original Paper

Abstract

Molecular dynamics (MD) simulations allow determining internal flexibility of molecules at atomic level. Using ab initio Born–Oppenheimer molecular dynamics (BOMD), one can simulate in a reasonable time frame small systems with hundreds of atoms, usually in vacuum. With quantum mechanics/molecular mechanics (QM/MM) or full-atom molecular dynamics (FAMD), the influence of the environment can also be simulated. Here, we compare three types of MD calculations: ab initio BOMD, hybrid QM/MM, and classical FAMD. As a model system, we use a small antibiotic molecule, clindamycin, which is one of the lincosamide antibiotics. Clindamycin acquires two energetically stable forms and we investigated the transition between these two experimentally known conformers. We performed 60-ps BOMD simulations in vacuum, 50-ps QM/MM, and 100-ns FAMD in explicit water. The transition between two antibiotic conformers was observed using both BOMD and FAMD methods but was not noted in the QM/MM simulations.

Keywords

Antibiotics Lincosamides Clindamycin Born–Oppenheimer molecular dynamics BOMD Quantum mechanics/molecular mechanics QM/MM Full-atom molecular dynamics FAMD 

Notes

Acknowledgments

Computational resources were provided by the Interdisciplinary Centre for Mathematical and Computational Modelling of the University of Warsaw by grants G31-4 G31-13 and G59-9. The authors acknowledge support from the University of Warsaw (CeNT/BST), National Science Centre (DEC-2012/05/B/NZ1/00035 and UMO-2013/09/N/ST4/00932).

Supplementary material

894_2015_2881_MOESM1_ESM.pdf (923 kb)
(PDF 922 KB)

References

  1. 1.
    Becke A (1992) Densityfunctional thermochemistry. III. the role of exact exchange. J Chem Phys 98(7):5648–5652CrossRefGoogle Scholar
  2. 2.
    Becke D (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A 38:3098–3100CrossRefGoogle Scholar
  3. 3.
    Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H, Shindyalov I, Bourne P (2000). Nucleic Acids Res 28:235–242CrossRefGoogle Scholar
  4. 4.
    Boero M, Ikeda T, Ito E K T (2006) Hsc70 ATPase: an insight into water dissociation and joint catalytic role of K + and Mg 2+ metal cations in the hydrolysis reaction. J Am Chem Soc 128(51):16,798–16,807CrossRefGoogle Scholar
  5. 5.
    Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126(1):014,101–1–014,101–6CrossRefGoogle Scholar
  6. 6.
    Car R, Parrinello M (1985) Unified approach for molecular dynamics and density-functional theory. Phys Rev Lett 55(2471):2471–2474CrossRefGoogle Scholar
  7. 7.
    Case D, Darden T, Cheatham III T, Simmerling C, Wang J, Duke R, Luo R, Walker R, Zhang W, Merz K, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz A, Kolossvry K I W, Paesani F, Vanicek J, Wolf R, Liu J, Wu X, Brozell S, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M, Cui G, Roe D, Mathews M DHS, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman P (2012) Amber 12. University of California, San FranciscoGoogle Scholar
  8. 8.
    Case D, Cheatham T I, Darden T, Gohlke H, Luo R, Merz K, Onufriev A, Simmerling C, Wang B, Woods R (2005) The amber biomolecular simulation programs. J Comput Chem 26:1668–1688CrossRefGoogle Scholar
  9. 9.
    Darden T, Perera L, Li L, Pedersen L (1999) New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations. Structure 7(3):R55—R60CrossRefGoogle Scholar
  10. 10.
    Derat E, Shaik S, Rovira C, Vidossich P, Alfonso-Prieto M (2007) The effect of a water molecule on the mechanism of formation of compound 0 in horseradish peroxidase. J Am Chem Soc 129(20):6346–6347CrossRefGoogle Scholar
  11. 11.
    Duan Y, Wu C, Chowdhury S, Lee M, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comp Chem 24:1999–2012CrossRefGoogle Scholar
  12. 12.
    Dunklea J, Xiongb L, Mankinb A, Catea J (2010) Structures of the Escherichia coli ribosome with antibiotics bound near the peptidyl transferase center explain spectra of drug action. PNAS 107(40):17,152–17,157CrossRefGoogle Scholar
  13. 13.
    Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, Scalmani G, Barone V, Mennucci B, Petersson G, Nakatsuji H, Caricato M, Li X, Hratchian H, Izmaylov A, Bloino J, Zheng G, Sonnenberg J, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery J, Peralta J, Ogliaro F, Bearpark M, Heyd J, Brothers E, Kudin K, Staroverov V, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant J, Iyengar S, Tomasi J, Cossi M, Rega N, Millam J, Klene M, Knox J, Cross J, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann R, Yazyev O, Austin A, Cammi R, Pomelli C, Ochterski J, Martin R, Morokuma K, Zakrzewski V, Voth V, Salvador P, Dannenberg J, Dapprich S, Daniels AF, Foresman J, Ortiz J, Cioslowski J, Fox D (2003) Gaussian 09 Revision A.1. Gaussian Inc. Wallingford, CT 2009Google Scholar
  14. 14.
    Goedecker S, Teter M, Hutter J (1996) Separable dual-space Gaussian pseudopotentials. Phys Rev B 54(3):1703–1710CrossRefGoogle Scholar
  15. 15.
    Hoe W, Cohen A, Handy N (2001) Assessment of a new local exchange functional OPTX. Chem Phys Lett 341:319–328CrossRefGoogle Scholar
  16. 16.
    Hohenberg P, Kohn W (1964) Inhomogeneous electron gas. Phys Rev B 136(3B):B864—B891CrossRefGoogle Scholar
  17. 17.
    Humphrey W, Dalke A, Schulten K (1996) VMD—visual molecular dynamics. J Mol Graph 14:33–38CrossRefGoogle Scholar
  18. 18.
    Jorgensen W, Chandrasekhar J, Madura J, Impey R, Klein M (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79(2):926–935CrossRefGoogle Scholar
  19. 19.
    Kirchhoff F, Kresse G, Gilla M (1997) Structure and dynamics of liquid selenium. Phys Rev B 57(17):10, 482–10,495CrossRefGoogle Scholar
  20. 20.
    Kohn W, Sham L (1965) Self-consistent equations including exchange and correlation effects. Phys Rev A 140(4A):A1133—A1138CrossRefGoogle Scholar
  21. 21.
    Kulczycka-Mierzejewska K, Trylska J, Sadlej J (2012) Quantum mechanical studies of lincosamides. J Mol Model 18(6):2727–2740CrossRefGoogle Scholar
  22. 22.
    Lee C, Yang W, Parr R (1988) Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789CrossRefGoogle Scholar
  23. 23.
    Liljas A (2004) Structural aspects of protein synthesis. World Scientific Publishing CompanyGoogle Scholar
  24. 24.
    Morar M, Bhullar K, Hughes D, Junop M, Wright G (2009) Structure and mechanism of the lincosamide antibiotic adenylyltransferase LinB. Structure 17(12):1649–1659CrossRefGoogle Scholar
  25. 25.
    Mura C, McCammon J (2008) Molecular dynamics of a.kappa.b DNA element: base flipping via cross-strand intercalative stacking in a microsecond-scale simulation. Nucleic Acids Research 36(15):4941–4955CrossRefGoogle Scholar
  26. 26.
    Pearlman D, Case D, Caldwell J, Ross W, Cheatham T, DeBolt S, Ferguson D, Seibel G, Kollman P (1995) Amber, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Commun 91:1–41CrossRefGoogle Scholar
  27. 27.
    Perdew J, Burke K, Ernzerhof M (1996) Generalized gradient approximation made simple. Phys Rev Lett 7(18):3865–3868CrossRefGoogle Scholar
  28. 28.
    Perdew J, Ruzsinszky A, Csonka G, Vydrov O, Scuseria G, Constantin L, Zhou X, Burke K (2008) Restoring the density-gradient expansion for exchange in solids and surfaces. Phys Rev Lett 100(13):136, 406–136,409CrossRefGoogle Scholar
  29. 29.
    Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel R, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comp Chem 26(16):1781– 1802CrossRefGoogle Scholar
  30. 30.
    Ryckaert J, Ciccotti G, Berendsen H (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comp Phys 23(3):327–341CrossRefGoogle Scholar
  31. 31.
    Schlick T (2010) Molecular modeling and simulation: an interdisciplinary guide (Interdisciplinary Applied Mathematics). SpringerGoogle Scholar
  32. 32.
    Schlunzen F, Zarivach R, Harms J, Bashan A, Tocilj A, Albrecht R, Yonath A, Franceschi F (2001) Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413:814–821CrossRefGoogle Scholar
  33. 33.
    Tenson T, Lovmar M, Ehrenberg M (2003) The mechanism of action of macrolides, lincosamides and reveals the nascent peptide exit path in the ribosome. JMB 330(5):1005–1014CrossRefGoogle Scholar
  34. 34.
    Tomasi J, Mennucci B, Cammi R (2005). Chem Rev 105(8):2999–3093CrossRefGoogle Scholar
  35. 35.
    Tu D, Blaha G, Moore P, Steitz T (2005) Structures of MLS B K antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance. Cell 121 (2):257– 270CrossRefGoogle Scholar
  36. 36.
    VandeVondele J, Krack M, Mohamed F, Parrinello M, Chassaing T, Hutter J (2005) Quickstep: fast and accurate density functional calculations using a mixed Gaussian and plane waves approach. Comp Chem Comm 167(2):103–128Google Scholar
  37. 37.
    Verdier L, Bertho JGG-B, Girault J (2000) Lincomycin and clindamycin conformations. A fragment shared by macrolides, ketolides and lincosamides determined from TRNOE ribosome-bound conformations. Bioorg & Med Chem 8:1225–1243CrossRefGoogle Scholar
  38. 38.
    Vidossich P, Alfonso-Prieto M, Carpena X, Loewen P, Fita I, Rovira C (2007) Versatilityoftheelectronicstructureofcompoundiincatalase peroxidases. J Am Chem Soc 129 44:13,436–13,446CrossRefGoogle Scholar
  39. 39.
    Wang I, Karplus M (1973) Dynamics of organic reactions. J Am Chem Soc 95(24):8160–8164CrossRefGoogle Scholar
  40. 40.
    Wang J, Cieplak P, Kollman P (2000) How well does a restrained electrostatic potential (resp) model perform in calculating conformational energies of organic and biological molecules J Comp Chem 21(12):1049–1074CrossRefGoogle Scholar
  41. 41.
    Warshel W, Karplus M (1975) Semiclassical trajectory approach to photoisomerization. Chem Phys Lett 32(1):11–17CrossRefGoogle Scholar
  42. 42.
    Zhang Y, Yang W (1998) Comment on generalized gradient approximation made simple. Phys Rev Lett 80(4):890–890CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Katarzyna Kulczycka-Mierzejewska
    • 1
    • 2
  • Joanna Trylska
    • 3
  • Joanna Sadlej
    • 4
    Email author
  1. 1.Interdisciplinary Centre for Mathematical and Computational ModellingUniversity of WarsawWarsawPoland
  2. 2.College of Inter-faculty Individual Studies in Mathematics and Natural ScienceUniversity of WarsawWarsawPoland
  3. 3.Centre of New TechnologiesUniversity of WarsawWarsawPoland
  4. 4.Faculty of ChemistryUniversity of WarsawWarsawPoland

Personalised recommendations