PM3&ZnB/SCRF optimized aqueous structure with 1 explicit water Zinc ASP7–HIS13–HIS14–HIS6 PM3&ZnB/SCRF optimized aqueous structure 7) 7) A more densely packed structure is formed, with His6 turned to complete a tetrahedral coordination around the Zn 2+ ion. Asp7 is still bound to the metal in this instance. Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala Linear scaling semiempirical molecular orbital calculations on the complexation of zinc ions by the Alzheimer’s  -amyloid peptide Zoltán A. Fekete 1, Eufrozina A. Hoffmann 2, Tamás Körtvélyesi 1,2, Botond Penke 3 1 HPC Group, University of Szeged, Hungary 2 Department of Physical Chemistry, University of Szeged, Hungary 3 SZTE-MTA Research Group on Supramolecular and Nanostructured Materials, Szeged, Hungary Conclusions and outlook We have validated the use of linear scaling ‘DivCon/ZnB’ method of Merz et al. for handling zinc metallopeptides. We have validated the use of linear scaling ‘DivCon/ZnB’ method of Merz et al. for handling zinc metallopeptides. The current investigation revealed a novel multi-functional role played by Asp7 in the process of zinc binding by Aβ. The current investigation revealed a novel multi-functional role played by Asp7 in the process of zinc binding by Aβ. It was demonstrated that this protocol makes feasible a quantum chemical treatment of systems containing hundreds of amino acid residues: on our commodity cluster, typical CPU times for one SCF cycle are well under 1 minute/residue! It was demonstrated that this protocol makes feasible a quantum chemical treatment of systems containing hundreds of amino acid residues: on our commodity cluster, typical CPU times for one SCF cycle are well under 1 minute/residue! This performance will enable studying Aβ aggregates with several monomer units by ‘DivCon/ZnB’; a further development of the protocol (incorporating extended General AMBER FF augmented with metallo-protein parameters from Hoops and Merz) can also handle dynamics with QM/MD. This performance will enable studying Aβ aggregates with several monomer units by ‘DivCon/ZnB’; a further development of the protocol (incorporating extended General AMBER FF augmented with metallo-protein parameters from Hoops and Merz) can also handle dynamics with QM/MD. We made, and are releasing, user tools for molecular coordinate processing to streamline work with DivCon format: We made, and are releasing, user tools for molecular coordinate processing to streamline work with DivCon format: Partial funding was provided by the Hungarian Scientific Research Fund (OTKA/61577), and by the Hungarian National Office for Research and Technology (grants RET 08/2004, ALAP /2005). Database structure + calculated protonation 1) Detail of structure, PM3&ZnB optimized 2) 3) 1) Starting structure is taken from the PDB. An initial guess for the protonation state is made with a simple Poisson-Boltzmann calculation. This indicated a possibly unusual charge for His14, sensitive to the ionic strenght and permittivity of the medium… 2) The initial crude coordinates are refined by the DivCon routine (implemented in AMBER9), using the ‘ZnB’ reparametrization of the PM3 Hamiltonian. No dielectric is considered at this stage… 3) Exploring the micro-hydratation of a putative metal binding region: this is a snapshot of a pocket being formed by His6- Asp7-His14. The structure is optimized in implicit aqueous media (SCRF solvent model), with one explicit H 2 O added… PM3&ZnB/SCRF optimized aqueous structure with 2 explicit waters 4) 4) Building up the quasi- structural water network within the His6-Asp7-His14 pocket: a second explicit H 2 O is put in. The hydrogen-bonding solvent interactions may facilitate the arrangement favorable for metal binding. Zinc ASP7–HIS14 PM3&ZnB/SCRF optimized aqueous structure 5) 5) This is one possible arrangement for the initial embedding of a Zn 2+ ion within the His6-Asp7-His14 pocket (for simplicity, explicit H 2 O molecules are not yet inserted here). The complexing ion can stabilize a rearranged structure developing subsequently, with a twist of the backbone moving the His13 residue into the vicinity of this region. Zinc ASP7–HIS13–HIS14 PM3&ZnB/SCRF optimized aqueous structure 6) 6) In this optimized structure a possible binding motif for Zn 2+ ion is depicted. The arrangement of His13 and His14 coupled by the zinc is often considered a precondition of aggregating A ß. It is interesting to note the unusually active role of Asp7 in the forming of this complex (while His6 is merely a spectator in this instance). Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala