A micro-environmental study of the Zn +2 –Aβ 1–16 structural properties A. Maiorana a , T. Marino b , V. Minicozzi c, ⁎, S. Morante c , N. Russo b a Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy b Dipartimento di Chimica — Università della Calabria, Cubo 12C Via P. Bucci, 87036 Arcavacata di Rende, CS, Italy c Dipartimento di Fisica Università di Roma “Tor Vergata” & INFN, Sezione di Roma “Tor Vergata”, Via della Ricerca Scientifica, 1, 00133 Rome, Italy HIGHLIGHTS • We performed classical MD of Ab(1–16) in gas phase and in water. • We used three different classical force fields. • We performed QM/MM optimization of the MD simulated systems. • We computed partial charges of QM/ MM optimized systems. • FF3 partial charges match those coming from QM computation and Zn geometry fits the experimentally known metal coordination GRAPHICAL ABSTRACT abstract article info Article history: Received 15 April 2013 Received in revised form 14 June 2013 Accepted 7 July 2013 Available online 23 July 2013 Keywords: Metal Molecular dynamics QM/MM Abeta peptide Alzheimer Relying on a combination of classical molecular dynamics and hybrid QM/MM computational methods, we study the influence of the nature of the local physico-chemical environment on the structural features of β-amyloid peptides complexed with Zn +2 ions. The analysis is carried out by comparing among themselves different Zn +2 -ligand force fields and studying their influence on metal coordination and long-range peptide folding. The system in the non-physiological so-called “gas phase” (no solvent) was also simulated with the purpose of identifying to what extent, if at all, the solvent can affect the Zn coordination mode, besides its long-range struc- tural properties. There are two main results of this investigation. The first is that the Zn +2 coordination mode in classical molecular dynamics simulations markedly depends on the partial charge attributed to the ion and the atoms surrounding it. Comparing with experiments, it is possible to identify the most appropriate Zn +2 force field for the Zn +2 –Aβ 1–16 complex in study. Secondly, although the presence of water naturally influences the peptide folding propensity, it does not affect the structure of the Zn +2 inner coordination shell. A useful way to validate classical results and in particular those referring to the structural differences visible when different force fields are employed, was to use a hybrid QM/MM optimization step. When the classical system configura- tions are submitted to such a quantum minimization step, the geometries of the resulting Zn +2 site turn out to be all very similar and structurally in good agreement with what is experimentally known. © 2013 Elsevier B.V. All rights reserved. 1. Introduction A key feature in the development of the Alzheimer disease (AD) is the formation of plaques made by β-amyloid peptide (Aβ-peptide) Biophysical Chemistry 182 (2013) 86–93 ⁎ Corresponding author. Tel.: +39 06 72594554; fax: +39 06 2023507. E-mail address: minicozzi@roma2.infn.it (V. Minicozzi). 0301-4622/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bpc.2013.07.002 Contents lists available at ScienceDirect Biophysical Chemistry journal homepage: http://www.elsevier.com/locate/biophyschem