Molecular dynamics analysis of HIV-1 matrix protein: Clarifying differences between crystallographic and solution structures Hugo Verli a,b, * , Alexandre Calazans c , Rodrigo Brindeiro c , Amilcar Tanuri c , Jorge A. Guimara ˜es b a Faculdade de Farma ´cia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre 90610-000, RS, Brazil b Centro de Biotecnologia, Univerdade Federal do Rio Grande do Sul, Av. Bento Gonc ¸alves, 9500, CP 15005, Porto Alegre 91500-970, RS, Brazil c Departmento de Gene ´tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro, RJ 21944-970, Brazil Received 19 June 2006; received in revised form 12 September 2006; accepted 20 September 2006 Available online 26 September 2006 Abstract One of the main structural features of the mature HIV-1 virion is the matrix protein (p17). This partially globular protein presents four helixes centrally organized and a fifth one, H5, projecting away from the packed bundle of helixes. Comparison between solution and crystallographic data of p17 indicates a 6 A ˚ displacement of a short 3 10 helix and a partial unfolding of H5 in solution related to crystal. While the behavior of the 3 10 helix has been previously addressed to virion assembly, the relevance and origin of H5 partial unfolding is possibly related to the contacts between p17 and other viral elements, such as p24. In this context, we present a 40 ns conformational sampling of monomeric p17 using molecular dynamics simulations. The performed simulations presented a progressive conversion of the p17 crystallographic structure to the NMR conformation, suggesting that the biological form of this protein may have its C-terminal portion partially unfolded. # 2006 Elsevier Inc. All rights reserved. Keywords: Molecular dynamics; HIV-1 matrix protein; Crystallographic contacts; p17; p24 1. Introduction The structural features of the mature HIV-1 virion include a lipid bilayer envelope, surface glycoproteins (gp120) anchored to the virus through interactions with a transmem- brane protein (gp41), a matrix shell (p17), and a conical capsid core (p24). In addition, two copies of the unspliced viral genome, stabilized by the nucleocapsid protein (p7), occur in the center of the virus together with viral enzymes (protease, reverse transcriptase and integrase) and accessory proteins (Nef, Vif, and Vpr) [1]. While a considerable amount of information is already known about these components in its isolated forms [1–9], the arrangement of such molecules to build the mature HIV-1 virion is, so far, not completely elucidated [10]. The HIV-1 matrix protein (p17) is a structural molecule, partially globular, composed by five a-helices (Fig. 1). The helixes H1, H2 and H3 are organized around the central and buried H4 [5], while H5 is projected from the packed helical bundle, making the C-terminal region of the protein distinct from its globular N-terminal (Fig. 2A). Additional elements on the secondary structure of this protein include the 3 10 -helix H2 0 and the mixed a/3 10 -helix H3 0 [5]. Current data, based on crystallographic experiments [5], electron microscopy observations [3,7], and docking calcula- tions [11] point to a trimeric organization of p17 monomers in the mature virion. Such organization appears to be also used by others HIV-1 structural proteins [10], in an organization defined by the Gag precursor. On the other hand, the precise contacts occurring between p17 and p24 remains poorly resolved [10]. One necessary step to resolve such contacts includes the precise elucidation of the three-dimensional structures of p17 and p24. Although there are currently several structural data of these molecules [2,4–6,12], some structural aspects of these proteins emerge from comparison between its solution and crystallographic forms. In fact, previous studies had reported a www.elsevier.com/locate/JMGM Journal of Molecular Graphics and Modelling 26 (2007) 62–68 * Corresponding author at: Faculdade de Farma ´cia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre 90610-000, RS, Brazil. Tel.: +55 51 3316 7770; fax: +55 51 3316 7309. E-mail address: hverli@cbiot.ufrgs.br (H. Verli). 1093-3263/$ – see front matter # 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2006.09.009