Molecular dynamics of mouse and Syrian hamster PrP: Implications for activity

Abstract

Molecular dynamics computer simulations have been performed on Mouse (Mo) and Syrian Hamster (SHa) prion proteins. These proteins differ, primarily, in that the SHa form incorporates additional residues at the C-terminus and also includes a segment of the unstructured N-terminal region that is required for infectivity. The 1-ns simulations have been analyzed by using a combination of dynamical cross-correlation maps, residue-residue contact plots, digital filtering, and residue-based root-mean-square deviations. The results show that the extra residues present in the SHa form at the C- and N-termini produce changes in the stability of key regions of the protein. The loop region between strand S2 and helix B that contains part of the proposed discontinuous binding site for the chaperone, protein X, is found to be more stable in SHa than in the Mo protein; these results are consistent with the NMR data of James et al. (James et al. Proc Natl Acad Sci USA 1997;94:10086-10091). In addition, a degree of flexibility within the region between and including strand S1 and helix A is also shown in SHa, which is not present in the Mo form; the cross-correlation maps suggest that this is a consequence of the additional unstructured N-terminal region. Furthermore, the extra residues in the N-terminal region of SHa are found to form a beta-bridge with the beta-sheet, within which critical point mutations associated with prion diseases lie. The implications of these results for the conformational interconversion pathway of the prion protein are discussed.

Checking the pH-Induced Conformational Transition of Prion Protein by Molecular Dynamics Simulations: Effect of Protonation of Histidine Residues

“…The most relevant structural changes involve the destructuration of the C-terminal part of helix B (residues 188-194). Until now it has instead been assumed that HB and HC constitute the stable core of the protein whereas the conformational transition to the b-rich form involves helix A (Parchment and Essex, 2000;Alonso et al, 2001). However the results of our computations are in line with NMR (Donne et al 1997;Zahn et al, 2000) and x-ray (Knaus et al, 2001) data revealing a significant flexibility of the C-terminal end of HB, with a very recent sequence alignment study predicting that the C-terminal residues in HB are frustrated in their helical state (Dima and Thirumalai, 2002), and also with MD simulations by Santini and Derreumaux (2004) which shows that unfolding of HA is not an early step in PrP interconversion and that there is no evidence that HB and HC are more stable than HA.…”

“…We further investigate this hypothesis in this study, checking how human PrP C globular domain reacts to mildly acidic conditions, i.e., much less acidic than that investigated by Alonso et al (Alonso et al, 2001 and Sekijima et al (2003), in which protonation should involve mainly histidine residues. We tackle this goal by means of molecular dynamic (MD) simulations (van Gunsteren and Berendsen, 1990;Braatz et al, 1992;Fox and Kollman, 1996), which have already been fruitfully used to investigate the dynamical behavior of prion proteins (Zuegg and Gready, 1999;Billeter and Wüthrich, 2000;Parchment and Essex, 2000;Alonso et al, 2001Alonso et al, , 2002DeMarco and Daggett, 2004;Santini and Derreumaux, 2004).…”

Mapping the early steps in the pH-induced conformational conversion of the prion protein

“…In addition, it is not possible experimentally to determine the mechanism of conversion at high resolution. Two short molecular dynamics simulation studies of PrP C at neutral pH have been reported recently (28,29). Here we present 10-ns simulations of PrP C at neutral and low pH and evaluate the connection between low pH and increases in ␤-structure.…”

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

“…The first studies utilizing this technique involved analysis of correlated motions in cytochrome c (McCammon, 1984), ribonuclease A with two different substrates (Brünger et al, 1985), HIV-1 protease (Harte et al, 1990;Harte et al, 1992;Swaminathan et al, 1991), and BPTI (Ichiye and Karplus, 1991). Since these pioneering studies, cross-correlations and DCCMs have been used to analyze the fluctuations of many diverse systems, including proteins (Arcangeli et al, 1999;Parchment and Essex, 2000;Arcangeli et al, 2001;Rizzuti et al, 2001;Young et al, 2001;Luo and Bruice, 2002;Zoete et al, 2002), protein-nucleic acid complexes (Suenaga et al, 2000;Trylska et al, 2005), and enzymes (Bahar et al, 1997;Radkiewicz and Brooks III, 2000;Rod et al, 2003;Sulpizi et al, 2003;Agarwal, 2004;Gunasekaran and Nussinov, 2004;Schiøtt, 2004;Wong et al, 2004;Fuxreiter et al, 2005;Gorfe and Caflisch, 2005;Ma et al, 2005). A recent study analyzing both the B1 domain of protein G and ubiquitin suggests the correlated motions obtained from MD simulations agree well with measured NMR data (Lange et al, 2005).…”