title: A simulation strategy for the atomistic modeling of flexible molecules covalently tethered to rigid surfaces: application to peptides.
abstract: A computational strategy to model flexible molecules tethered to a rigid inert surface is presented. The strategy is able to provide uncorrelated relaxed microstructures at the atomistic level. It combines an algorithm to generate molecules tethered to the surface without atomic overlaps, a method to insert solvent molecules and ions in the simulation box, and a powerful relaxation procedure. The reliability of the strategy has been investigated by simulating two different systems: (i) mixed monolayers consisting of binary mixtures of long-chain alkyl thiols of different lengths adsorbed on a rigid inert surface and (ii) CREKA (Cys-Arg-Glu-Lys-Ala), a short linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, covalently tethered to a rigid inert surface in aqueous solution. In the first, we examined the segregation of the two species in the monolayers using different long-chain:short-chain ratios, whereas in the second, we explored the conformational space of CREKA and ions distribution considering densities of peptides per nm(2) ranging from 0.03 to 1.67. Results indicate a spontaneous segregation in alkyl thiol monolayers, which enhances when the concentration of longest chains increases. However, the whole conformational profile of CREKA depends on the number of molecules tethered to the surface pointing out the large influence of molecular density on the intermolecular interactions, even though the bioactive conformation was found as the most stable in all cases.
authors.affiliation: Department d'Enginyeria Química, Facultat de Química, Universitat de Barcelona, Martí Franques 1, Barcelona E-08028, Spain. curco@angel.qui.ub.es
authors.forename: David
authors.initials: D
authors.lastname: Curcó
authors.forename: David
authors.initials: D
authors.lastname: Zanuy
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Carlos
authors.initials: C
authors.lastname: Alemán
mesh_terms: D000327:Adsorption; D000465:Algorithms; D007477:Ions / Q000737:chemistry; D056004:Molecular Dynamics Simulation / Q000639:trends; D009842:Oligopeptides / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D007477:Ions; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; C542438:cysteinyl-arginyl-glutamyl-lysyl-alanyl
references.citation: J Phys Chem B. 2008 Jul 24;112(29):8692-700
references.pmid: 18588341
references.citation: Oncogene. 2000 Dec 11;19(53):6130-7
references.pmid: 11156526
references.citation: Nature. 2004 Jun 10;429(6992):629-35
references.pmid: 15190345
references.citation: J Chem Phys. 2004 Nov 15;121(19):9744-52
references.pmid: 15538898
references.citation: Biopolymers. 2009;92(2):83-93
references.pmid: 19051312
references.citation: Small. 2009 Mar;5(6):694-700
references.pmid: 19263431
references.citation: J Comput Chem. 2002 May;23(7):685-96
references.pmid: 11948586
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12617-21
references.pmid: 12235356
references.citation: Blood. 2010 Oct 14;116(15):2847-56
references.pmid: 20587786
references.citation: Cancer Cell. 2003 Nov;4(5):383-91
references.pmid: 14667505
references.citation: Nature. 1996 Mar 28;380(6572):364-6
references.pmid: 8598934
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1317-24
references.pmid: 16489089
references.citation: J Comput Chem. 2007 Jul 30;28(10):1743-9
references.pmid: 17340605
references.citation: Nat Rev Cancer. 2002 Feb;2(2):83-90
references.pmid: 12635171
references.citation: J Comput Aided Mol Des. 1992 Apr;6(2):175-90
references.pmid: 1624957
references.citation: Biomed Microdevices. 2004 Dec;6(4):297-309
references.pmid: 15548877
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):932-6
references.pmid: 17215365
references.citation: Nano Lett. 2006 Apr;6(4):669-76
references.pmid: 16608262