Abstract
We here report a combined quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) study on the binding interactions between the αVβ3 integrin and eight cyclic arginine-glycine-aspartate (RGD) containing peptides. The initial conformation of each peptide within the binding site of the integrin was determined by docking the ligand to the reactive site of the integrin crystal structure with the aid of docking software FRED. The subsequent QM/MM MD simulations of the complex structures show that these eight cyclic RGD-peptides have a generally similar interaction mode with the binding site of the integrin to the cyclo(RGDf-N[M]V) analog found in the crystal structure. Still, there are subtle differences in the interactions of peptide ligands with the integrin, which contribute to the different inhibition activities. The averaged QM/MM protein-ligand interaction energy (IE) is remarkably correlated to the biological activity of the ligand. The IE, as well as a three-variable model which is somewhat interpretable, thus can be used to predict the bioactivity of a new ligand quantitatively, at least within a family of analogs. The present study establishes a helpful protocol for advancing lead compounds to potent inhibitors.
Similar content being viewed by others
References
Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687
Zanardi F, Burreddu P, Rassu G, Auzzas L, Battistini L, Curti C et al. (2008) Discovery of subnanomolar arginine-glycine-aspartate-based αVβ3/αVβ5 integrin binders embedding 4-aminoproline residues. J Med Chem 51(6):1771–1782
Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL et al (2001) Crystal structure of the extracellular segment of integrin αVβ3. Science 294(5541):339–345
Arnaout MA, Goodman SL, Xiong JP (2002) Coming to grips with integrin binding to ligands. Current Opin Cell Biol 14(5):641–652
Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL et al. (2002) Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand. Science 296:151–155
Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119:3901–3903
Spitaleri A, Mari S, Curnis F, Traversari C, Longhi R, Bordignon C et al. (2008) Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin. J Biol Chem 283(28):19757–19768
Jin H, Varner J (2004) Integrins: roles in cancer development and as treatment targets. Brit J Cancer 90(3):561–565
Bella J, Humphries MJ (2005) Cα -H···O = C hydrogen bonds contribute to the specificity of RGD cell-adhesion interactions. BMC Struct Biol 5:4
Paradise RK, Lauffenburger DA, van Vliet KJ (2011) Acidic extracellular pH promotes activation of integrin αvβ3. PloS one 6(1):e15746
Elliot D, Henshaw E, MacFaul PA, Morley AD, Newham P, Oldham K et al. (2009) Novel inhibitors of the αvβ3 integrin-lead identification strategy. Bioorg Med Chem Lett 19:4832–4835
Sukopp M, Marinelli L, Heller M, Brandl T, Goodman SL, Hoffmann RW et al (2002) Designed beta turn mimic based on the allylic strain concept: evaluation of structural and biological features by incorporation into a cyclic RGD peptide (Cyclo(-L-arginylglycyl-L- α-aspartyl-)). Helv Chim Acta 85(12):4442–4452
Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M et al (2005) Noninvasive visualization of the activated αvβ3 integrin in cancer patients by positron emission tomography and [18F] galacto-RGD. PLoS Med 2(3):e70
Varner JA, Cheresh DA (1996) Integrins and cancer. Curr Opin Cell Biol 8(5):724–730
Takagi J (2004) Structural basis for ligand recognition by RGD (Arg-Gly-Asp)-dependent integrins. Biochem Soc T 32(Pt3):403–406
Locardi E, Mullen DG, Mattern RH, Goodman M (1999) Conformations and pharmacophores of cyclic RGD containing peptides which selectively bind integrin αVβ3. J Pept Sci 5(11):491–506
Tucker GC (2006) Integrins: molecular targets in cancer therapy. Curr oncol rep 8(2):96–103
Belvisi L, Bernardi A, Colombo M, Manzoni L, Potenza D, Scolastico C et al. (2006) Targeting integrins: insights into structure and activity of cyclic RGD pentapeptide mimics containing azabicycloalkane amino acids. Bioorg Med Chem 14(1):169–180
Gohlke H, Klebe G (2002) Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Angew Chem Int Ed Engl 41(15):2644–2676
Jorgensen WL (2009) Efficient drug lead discovery and optimization. Acc Chem Res 42(6):724–733
Xiang M, Cao Y, Fan W, Chen L, Mo Y (2012) Computer-aided drug design: lead discovery and optimization. Comb Chem High Throughput Screen 15(4):328–337
Schneidman-Duhovny D, Nussinov R, Wolfson HJ (2004) Predicting molecular interactions in silico: II. Protein-protein and protein-drug docking. Curr Med Chem 11(1):91–107
Shaikh SA, Jain T, Sandhu G, Latha N, Jayaram B (2007) From drug target to leads–sketching a physicochemical pathway for lead molecule design in silico. Curr Pharm Des 13(34):3454–3470
Zhou Z, Felts A, Friesner R, Levy R (2007) Comparative performance of several flexible docking programs and scoring functions: enrichment studies for a diverse set of pharmaceutically relevant targets. J Chem Inf Model 47(4):1599–1608
Adane L, Bharatam PV (2008) Modelling and informatics in the analysis of P. falciparum DHFR enzyme inhibitors. Curr Med Chem 15(16):1552–1569
Song CM, Lim SJ, Tong JC (2009) Recent advances in computer-aided drug design. Brief Bioinform 10(5):579–591
Mohan V, Gibbs AC, Cummings MD, Jaeger EP, DesJarlais RL (2005) Docking: successes and challenges. Curr Pharm Des 11(3):323–333
Alonso H, Bliznyuk AA, Gready JE (2006) Combining docking andmolecular dynamic simulations in drug design. Med Res Rev 26(5):531–568
Takeuchi H, Okazaki K (1990) Molecular dynamics simulation of diffusion of simple gas molecules in a short chain polymer. J Chem Phys 92(9):5643–5652
Kollman PA (1993) Free energy calculations: applications to chemical and biochemical phenomena. Chem Rev 93:2395–2417
Swanson JM, Henchman RH, McCammon JA (2004) Revisiting free energy calculations: a theoretical connection to MM/PBSA and direct calculation of the association free energy. Biophys J 86:67–74
Aquist J, Marelius J (2001) The linear interaction energy method for predicting ligand binding free energies. Comb Chem High Throughput Screen 4:613–626
Tan JJ, Cong XJ, Hu LM, Wang CX, Jia L, Liang XJ (2010) Therapeutic strategies underpinning the development of novel techniques for the treatment of HIV infection. Drug Discov Today 15(5–6):186–197
Reddy MR, Singh UC, Erion MD (2011) Use of a QM/MM-based FEP method to evaluate the anomalous hydration behavior of simple alkyl amines and amides: application to the design of FBPase inhibitors for the treatment of type-2 diabetes. J Am Chem Soc 133:8059–8061
Reddy MR, Erion MD (2007) Relative binding affinities of fructose-1, 6-bisphosphatase inhibitors calculated using a quantum mechanics-based free energy perturbation method. J Am Chem Soc 129(30):9296–9297
Menikarachchi LC, Gascón JA (2010) QM/MM approaches in medicinal chemistry research. Curr Top Med Chem 10:46–54
Warshel A, Levitt M (1976) Theoretical studies of enzymatic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J Mol Biol 103:227–249
Spiegela K, Magistrato A (2006) Modeling anticancer drug–DNA interactions via mixed QM/MM molecular dynamics simulations. Org Biomol Chem 4:2507–2517
Senn HM, Thiel W (2009) QM/MM methods for biomolecular systems. Angew Chem Int Ed Engl 48:1198–1229
Zhou T, Huang D, Caflisch A (2010) Quantum mechanical methods for drug design. Curr Top Med Chem 10:33–45
Xenides D, Randolf BR, Rode BM (2005) Structure and ultrafast dynamics of liquid water: a quantum mechanics/molecular mechanics molecular dynamics simulations study. J Chem Phys 122(17):174506
Alves CN, Marti S, Castillo R, Andres J, Moliner V, Tunon I et al. (2007) Calculation of binding energy using BLYP/MM for the HIV-1 integrase complexed with the S-1360 and two analogues. Bioorg Med Chem 15(11):3818–3824
Alzate-Morales JH, Contreras R, Soriano A, Tunon I, Silla E (2007) A computational study of the protein-ligand interactions in CDK2 inhibitors: using quantum mechanics/molecular mechanics interaction energy as a predictor of the biological activity. Biophys J 92(2):430–439
Brooks BR, Brooks CL III, Mackerell A Jr, Nilsson L, Petrella R, Roux B et al. (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30(10):1545–1614
Martin FP-D, Dumas R, Field MJ (2000) A hybrid-potential free-energy study of the isomerization step of the acetohydroxy acid isomeroreductase reaction. J Am Chem Soc 122(32):7688–7697
Gleeson MP, Hillier IH, Burton NA (2004) Theoretical analysis of peptidyl α-ketoheterocyclic inhibitors of human neutrophil elastase: insight into the mechanism of inhibition and the application of QM/MM calculations in structure-based drug design. Org Biomol Chem 2(16):2275–2280
Cui Q, Li G, Ma J, Karplus M (2004) A normal mode analysis of structural plasticity in the biomolecular motor F1-ATPase. J Mol Biol 340(2):345–372
Lin Y, Cao Z, Mo Y (2006) Molecular dynamics simulations on the Escherichia coli ammonia channel protein AmtB: mechanism of ammonia/ammonium transport. J Am Chem Soc 128(33):10876–10884
Rowley CN, Woo TK (2007) Generation of initial trajectories for transition path sampling of chemical reactions with ab initio molecular dynamics. J Chem Phys 126:024110
Cheng Y, Cheng X, Radic Z, McCammon JA (2007) Acetylcholinesterase: mechanisms of covalent inhibition of wild-type and H447I mutant determined by computational analyses. J Am Chem Soc 129(20):6562–6570
Hu H, Lu Z, Parks JM, Burger SK, Yang W (2008) Quantum mechanics/molecular mechanics minimum free-energy path for accurate reaction energetics in solution and enzymes: sequential sampling and optimization on the potential of mean force surface. J Chem Phys 128(3):034105
Rowley CN, Woo TK (2011) Counteranion effects on the zirconocene polymerization catalyst olefin complex from QM/MM molecular dynamics simulations. Organometallics 30:2071–2074
Alex A, Finn P (1997) Fast and accurate predictions of relative binding energies. J Mol Struct THEOCHEM 398:551–554
Ciancetta A, Genheden S, Ryde U (2011) A QM/MM study of the binding of RAPTA ligands to cathepsin B. J Comput Aided Mol Des 25(8):729–742
Beierlein FR, Michel J, Essex JW (2011) A simple QM/MM approach for capturing polarization effects in protein − ligand binding free energy calculations. J Phys Chem B 115:4911–4926
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(2):187–217
Word JM, Lovell SC, Richardson JS, Richardson DC (1999) Asparagine and glutamine: using hydrogen atom contacts in the choice of sidechain amide orientation. J Mol Biol 285:1735–1747
McGann M, Almond H, Nicholls A, Grant J, Brown F (2003) Gaussian docking functions. Biopolymers 68(1):76–90
McGaughey G, Sheridan R, Bayly C, Culberson J, Kreatsoulas C, Lindsley S et al. (2007) Comparison of topological, shape, and docking methods in virtual screening. J Chem Inf Model 47(4):1504–1519
McGann M (2011) FRED pose prediction and virtual screening accuracy. J Chem Inf Model 51:578–596
Bártová I, Koča J, Otyepka M (2008) Regulatory phosphorylation of cyclin-dependent kinase 2: insights from molecular dynamics simulations. J Mol Model 14(8):761–768
Wells GA, Müller IB, Wrenger C, Louw AI (2009) The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404. FEBS J 276(13):3517–3530
Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985) AM1: a new general purpose quantum mechanical molecular model. J Am Chem Soc 107(13):3902–3909
Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79(2):926–935
Brunger A, Brooks CL III, Karplus M (1985) Active site dynamics of ribonuclease. Proc Natl Acad Sci USA 82(24):8458–8462
Brooks CL III, Karplus M (1983) Deformable stochastic boundaries in molecular dynamics. J Chem Phys 79:6312–6325
Ryckaert JP, 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(3):327–341
Fernández-Recio J, Romero A, Sancho J (1999) Energetics of a hydrogen bond (charged and neutral) and of a cation-π interaction in apoflavodoxin1. J Mol Biol 290(1):319–330
Wintjens R, Liévin J, Rooman M, Buisine E (2000) Contribution of cation-π interactions to the stability of protein-DNA complexes. J Mol Biol 302(2):395–410
Zacharias N, Dougherty DA (2002) Cation-π interactions in ligand recognition and catalysis. Trends Pharmacol Sci 23(6):281–287
Lummis SCR, Beene DL, Harrison NJ, Lester HA, Dougherty DA (2005) A cation-π binding interaction with a tyrosine in the binding site of the GABAC receptor. Chem Biol 12(9):993–997
Xiu X, Puskar NL, Shanata JAP, Lester HA, Dougherty DA (2009) Nicotine binding to brain receptors requires a strong cation–π interaction. Nature 458(7237):534–537
Tantry S, Ding FX, Dumont M, Becker JM, Naider F (2010) Binding of fluorinated phenylalanine α-factor analogues to ste2p: Evidence for a cation-π binding interaction between a peptide ligand and its cognate G protein-coupled receptor. Biochemistry 49(24):5007–5015
Zhou Z, Madura JD (2004) Relative free energy of binding and binding mode calculations of HIV–1 RT inhibitors based on dock–MM–PB/GS. Proteins Struct Funct Bioinf 57(3):493–503
Bonnet P, Bryce RA (2004) Molecular dynamics and free energy analysis of neuraminidase–ligand interactions. Protein Sci 13(4):946–957
Humphrey W, Dalke A, Schulten K (1996) VMD - visual molecular dynamics. J Mol Graph 14(1):33–38
Acknowledgments
We would like to acknowledge the OpenEye Scientific Software for the academic license.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Xiang, M., Lin, Y., He, G. et al. Correlation between biological activity and binding energy in systems of integrin with cyclic RGD-containing binders: a QM/MM molecular dynamics study. J Mol Model 18, 4917–4927 (2012). https://doi.org/10.1007/s00894-012-1487-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00894-012-1487-z