TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 3243–3246 Pergamon Effect of temperature on peptide chain aggregation: an EPR study of model peptidyl-resins Suely C. F. Ribeiro, a Shirley Schreier, b Clovis R. Nakaie a and Eduardo M. Cilli a, * a Department of Biophysics, Universidade Federal de Sa ˜o Paulo, Rua 3 de Maio 100, 04044 -020, Sa ˜o Paulo, SP, Brazil b Department of Biochemistry, Institute of Chemistry, Universidade of Sa ˜o Paulo, C.P. 26077, 05513 -970, Sa ˜o Paulo, SP, Brazil Received 9 February 2001; revised 6 March 2001; accepted 12 March 2001 Abstract—The effect of temperature on the dynamics of peptide chains inside resin beads was monitored by electron paramagnetic resonance (EPR) spectroscopy. A two-component spectra was obtained for low and highly peptide-loaded model peptidyl-resins labeled with the paramagnetic aminoacid 2,2,6,6-tetramethyl-piperidine-N-oxyl-4-amino-4-carboxylic acid (TOAC), indicating the presence of strongly and weakly immobilized populations. Increasing levels of chain disaggregation were observed with increasing temperature, leading in some cases to a complete disappearance of the more immobilized population. The present findings demonstrate that EPR spectral parameters are highly sensitive to the solvation properties of labeled sites inside the resin matrix and can be of great value for the understanding of polymer-supported processes or reactions. © 2001 Elsevier Science Ltd. All rights reserved. Merrifield’s solid-phase peptide synthesis method 1 has been intensively investigated as a convenient model to improve the knowledge of the physicochemical basis of processes occurring throughout a polymeric matrix. In this context, emphasis has been recently given to resin- supported combinatorial chemistry for the development of new drugs. 2,3 Despite all these continuous efforts to optimize the peptide synthesis protocol, serious short- comings have intriguingly persisted. They are mainly related to incomplete coupling during peptide growth caused by chain aggregation inside the bead. 4 To over- come this problem alternative solid supports have been continuously proposed for peptide synthesis. 5,6 In addi- tion, attempts to establish the rules which govern resin solvation have been the object of several publications, as this property has been found to depend upon the Figure 1. Effect of temperature upon the EPR spectra of TOAC-labeled low (A) and highly loaded (B) VQAAIDYING-BHAR in DMF. * Corresponding author. E-mail: cilli.biof@infar.epm.br 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(01)00414-2