Send Orders of Reprints at reprints@benthamscience.net Current Physical Chemistry, 2013, 3, 187-198 187 Interaction and Reaction of the Antioxidant Mn III [Meso-Tetrakis(4-N- MethyI Pyridinium) Porphyrin] with the Apoptosis Reporter Lipid Phosphatidylserine Juliana C. Araújo-Chaves 1,2 , Cintia Kawai 1 , Antonio F. A. A. Melo 5 , Katia C. U. Mugnol 1 , Otaciro R. Nascimento 3 , Jeverson T. Arantes 4 , Frank N. Crespilho 5 and Iseli L. Nantes 1, * 1 Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP 09210-170, Brazil; 2 Centro Interdisciplinar de Investigação Bioquímica (CIIB), Universidade de Mogi das Cruzes, Av. Dr Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, SP, 08780-911, Brazil; 3 Grupo de Biofísica “Sergio Mascarenhas”, Universidade de São Paulo, Avenida Trabalhador São-carlense, 400, Sao Carlos, SP, 13560-970, Brazil; 4 Centro de Engenharia, Modelagem e Ciências Sociais Aplicadas (CECS) Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP 09210-170, Brazil; 5 Instituto de Química de São Carlos, Universidade de São Paulo, Avenida Trabalhador São-carlense, 400, São Carlos, SP, 13560-970, Brazil Abstract: In the present study, the binding of the cationic Mn III TMPyP [meso-tetrakis (4-N-methyl pyridinium) porphyrin] to negatively charged membrane models containing phosphatidylcholine (PC)/ phosphatidylserine (PS) and the porphyrin reactivity with PS-derived peroxides (LOOH) were evaluated. This investigation is relevant due to the participation of PS in cell signaling and apoptosis. Addition of PC/PS liposomes to Mn III TMPyP solutions led to spectral changes of the porphyrin electronic absorption spectrum suggestive of electrostatic interactions with the negatively charged interface provided by PS. The binding of Mn III TMPyP to PC/PS liposomes was corroborated by the quenching of the fluorophore merocyanine 540. In addition total energy calculations of saturated and unsaturated PS based on the spin- polarized variant of KS-DFT were used to support some experimental data. Cyclic voltammetry analysis revealed that the association to PC/PS liposomes shifted the redox potential of the Mn II /Mn III (+87 mV vs NHE, in aqueous buffered solution) couple to a more positive value to (+110 mV vs NHE). This event favors the oxidation of O 2 - to O 2 by the porphyrin. Mn III TMPyP was able to react with the lipid-derived peroxides as evidenced by spectral changes of the porphyrin consistent with the generation of a high valence state (Mn IV =O) of the catalyst. The spectral changes were not observed when biological lipids containing unsaturated PC and PS were replaced by the corresponding dipalmitoyl (DP)- derived: DPPC/DPPS. Keywords: Mn III TMPyP [meso-tetrakis (4-N-methyl pyridinium) porphyrin], Phosphatidylserine, Liposomes, Electronic absorption spectroscopy fluorescence spectroscopy, Electrostatic interaction, Superoxide dismutase mimetics. Dedicated to Henrik Bohr on the occasion of his 60th birthday (and published as part of the Quantum Nanobiology and Biophysical Chemistry special issue of CPC). INTRODUCTION Phosphatidylserine (PS) is an aminophospholipid that is restricted to the inner leaflet of the plasma membrane of most healthy cells [1-3]. In cell membranes, PS asymmetry results from translocation mechanisms provided by ‘flippases’ that drive unidirectionally the aminophospholipid to the cytoplasmatic face of the membrane [4-6]. The input of specific lipids by these transporters against concentration gradient requires coupling to ATP hydrolysis. Loss of PS asymmetry, i.e., transbilayer movement of the lipid from the cytoplasmic to the external face of the citoplasmic membranes, is an early manifestation of apoptosis and it is a result of both decreased aminophospholipid translocase activity and activation of a calcium-dependent scramblase, that promotes bidirectional transport of membrane lipids *Address correspondence to this author at the Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC, Rua Santa Adélia, 166, Santo André, SP 09210-170, Brazil; Tel: +55-11-4996-0174; E-mail: ilnantes@ufabc.edu.br [3-5,7,8]. Scramblases promote a bidirectional transport of lipids driven by a pre-existing transbilayer lipid gradient, and in the plasma membrane these transporters are activated by Ca 2+ . More details about catalyzed transbilayer lipid movements can be found in the minireview [8]. PS exposure is important for recognition and removal of cellular fragments in the events of erythrocyte senescence, apoptosis and platelet activation [9-11]. PS is probably not the sole ligand identified by phagocytes to remove apoptotic cells and PS exposure also occurs in non apoptotic cells [12-14]. Changes of the PS distribution in the lipid membraine play a role in signal transduction and modulate the activities of several membrane proteins. The PS distribution is also related to Ca 2+ and Na + uptake; P2X 7 -stimulated shedding of the homing receptor CD62L, a process required for lymphocyte migration to inflammatory sites [15]; and reversal of activity of the multidrug transporter P- glycoprotein. T lymphocytes that express low levels of the transmembrane tyrosine phosphatase have PS exposed at high levels on the membrane surface. Loss of membrane asymmetry with exposure of PS at cell surface also acts as a 1877-9476/13 $58.00+.00 © 2013 Bentham Science Publishers