PM3&ZnB/SCRF optimized aqueous structure with 1 explicit water Zinc complexing @...
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PM3&ZnB/SCRF optimized aqueous structure with 1 explicit water Zinc complexing @ ASP7–HIS13–HIS14– HIS6 PM3&ZnB/SCRF optimized aqueous structure 7) 7) 7 7 ) ) A more densely packed structure is formed, A more densely packed structure is formed, with His6 turned to complete a tetrahedral with His6 turned to complete a tetrahedral coordination around the Zn coordination around the Zn 2+ 2+ ion. ion. Asp7 Asp7 is still bound to the metal in this is still bound to the metal in this instance. instance. As p Se r Gl y Ty r Gl u Va l Hi s Hi s Gl n Ly s Le u Va l Ph e Ph e Al a Gl u As p Va l Gl y Se r As n Ly s Gl y Al a Il e Il e 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 < http://HPC.inf.hu/> Abstract The A lzheim er’sβ-amyloid peptide, Aβ , found as aggregated species in Alzheimer’s disease brain,is linked to the onset of dem entia.The toxic properties of Aβ depend on oligom erizationand aggregation. In addition, Aβ toxicity is aggrevated by the presence of zinc ions, which affect the secondary structure of the peptide.W e reportthe m odeling of possible interactions of zinc ions w ith Aβ(1-42) , one ofthe m ostam yloidogenic speciesknow n. The aim ofthe currentstudy w as tw ofold.First,in orderto theoretically handle several Aβ(1-42) m onom erstogether,a quantum chem icalm ethod w assoughtthatis capable ofhandling peptide system s com prised ofseveralhundreds residues.O urtests validated the sem iem piricalparam eterization ofzinc termed ZnB , developed by M erz et al. originally for treating zinc metalloenzymes, as capable of describing com plexation ofzinc by Aβ(1-42) .U sed in conjunction w ith the linearscaling sem iempirical program DivCon („ Divide and C onquer”),also by M erz et al.,fully quantum chem icaltreatm entof Aβ(1-42)oligom ersand theirzinc com plexesispossible, requiring only m odestcom puterresources. The second partofourprojectconsidered severalpossible structures along feasible pathw ays of form ing proto-aggregate m onomers upon complexing zinc with the apo-peptide. D ivC on/ZnB calculations probed putative intermediate conformations, which may play role in the eventual pathologicalm is-folding event.Likely participating ligand residues are suggested,besides the histidines which are the only ones confirmed unequivocally by experiments. Exploring the potential energy landscape atthisnovelleveloftheory providesnew structuralcluesforthe process. Conclusions and outlook Conclusions and outlook • We have validated the use of linear scaling ‘ We have validated the use of linear scaling ‘ DivCon/ZnB DivCon/ZnB ’ method of Merz ’ method of Merz et al. et al. for for handling zinc metallopeptides. handling zinc metallopeptides. • The current investigation revealed a novel multi-functional role played by Asp7 in the The current investigation revealed a novel multi-functional role played by Asp7 in the process of zinc binding by Aβ. process of zinc binding by Aβ. • It was demonstrated that this protocol makes feasible a quantum chemical treatment of 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 systems containing hundreds of amino acid residues: on our commodity cluster, typical CPU times for one SCF cycle are well under 1 minute/residue! times for one SCF cycle are well under 1 minute/residue! • This performance will enable studying Aβ aggregates with several monomer units by This performance will enable studying Aβ aggregates with several monomer units by ‘DivCon/ZnB’; ‘DivCon/ZnB’; a further development of the protocol (incorporating extended General AMBER FF augmented 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. 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 We made, and are releasing, user tools for molecular coordinate processing to streamline work with DivCon format: streamline work with DivCon format: <http://Zoli.alturl.com/moletools/> Partial funding was provided by the Hungarian Scientific Research Fund (OTKA/61577), Database structure + calculated protonation 1) 1) Detail of structure, PM3&ZnB optimized 2) 2) 3) 3) 1) Starting structure is taken from the PDB. An 1) Starting structure is taken from the PDB. An initial guess for the protonation state is made initial guess for the protonation state is made with a simple Poisson-Boltzmann calculation. with a simple Poisson-Boltzmann calculation. This indicated a possibly unusual charge for This indicated a possibly unusual charge for His14, sensitive to the ionic strenght and His14, sensitive to the ionic strenght and permittivity of the medium… permittivity of the medium… 2) The initial crude coordinates are refined by 2) The initial crude coordinates are refined by the DivCon routine (implemented in AMBER9), the DivCon routine (implemented in AMBER9), using the ‘ZnB’ reparametrization of the PM3 using the ‘ZnB’ reparametrization of the PM3 Hamiltonian. No dielectric is considered at this Hamiltonian. No dielectric is considered at this stage… stage… 3) Exploring the micro-hydratation of a putative 3) Exploring the micro-hydratation of a putative metal binding region: this is a snapshot of a metal binding region: this is a snapshot of a pocket being formed by His6-Asp7-His14. The pocket being formed by His6-Asp7-His14. The structure is optimized in implicit aqueous media structure is optimized in implicit aqueous media (SCRF solvent model), with one explicit H (SCRF solvent model), with one explicit H 2 O O added… added… PM3&ZnB/SCRF optimized aqueous structure with 2 explicit waters 4) 4) 4 4 ) ) Building up the Building up the quasi-structural water quasi-structural water network within the network within the His6-Asp7-His14 His6-Asp7-His14 pocket: pocket: a second a second explicit H explicit H 2 O O is is put in. The hydrogen- put in. The hydrogen- bonding solvent bonding solvent interactions may interactions may facilitate the facilitate the arrangement favorable arrangement favorable for metal binding. for metal binding. Zinc complexing @ ASP7–HIS14 PM3&ZnB/SCRF optimized aqueous structure 5) 5) 5 5 ) ) This is one possible This is one possible arrangement for the initial arrangement for the initial embedding of a Zn embedding of a Zn 2+ 2+ ion ion within the within the His6-Asp7-His14 His6-Asp7-His14 pocket (for simplicity, pocket (for simplicity, explicit H explicit H 2 O O molecules are molecules are not yet inserted here). The not yet inserted here). The complexing ion can stabilize complexing ion can stabilize a rearranged structure a rearranged structure developing subsequently, developing subsequently, with a twist of the backbone with a twist of the backbone moving the His13 residue moving the His13 residue into the vicinity of this into the vicinity of this region. region. Zinc complexing @ ASP7–HIS13–HIS14 PM3&ZnB/SCRF optimized aqueous structure 6) 6) 6 6 ) ) In this optimized In this optimized structure a possible structure a possible binding motif for Zn binding motif for Zn 2+ 2+ ion is depicted. The ion is depicted. The arrangement of His13 arrangement of His13 and His14 coupled by and His14 coupled by the zinc is often the zinc is often considered a considered a precondition of precondition of aggregating A aggregating A ß ß . It is . It is interesting to note interesting to note the unusually active the unusually active role of role of Asp7 Asp7 in the in the forming of this forming of this complex (while complex (while His His 6 is 6 is merely a spectator in merely a spectator in this instance). 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 As p Se r Gl y Ty r Gl u Va l Hi s Hi s Gl n Ly s Le u Va l Ph e Ph e Al a Gl u As p Va l Gl y Se r As n Ly s Gl y Al a Il e Il e 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 As p Se r Gl y Ty r Gl u Va l Hi s Hi s Gl n Ly s Le u Va l Ph e Ph e Al a Gl u As p Va l Gl y Se r As n Ly s Gl y Al a Il e Il e 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
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Transcript of PM3&ZnB/SCRF optimized aqueous structure with 1 explicit water Zinc complexing @...
PM3&ZnB/SCRF optimized aqueous structure with 1 explicit water
Zinc complexing @ASP7–HIS13–HIS14–
HIS6PM3&ZnB/SCRF
optimized aqueous structure
7)7)
77) ) A more densely packed structure is formed, with His6 A more densely packed structure is formed, with His6 turned to complete a tetrahedral coordination around turned to complete a tetrahedral coordination around the Znthe Zn2+2+ ion. ion. Asp7Asp7 is still bound to the metal in this instance. 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. Fekete1, Eufrozina A. Hoffmann2, Tamás Körtvélyesi1,2, Botond Penke3
1HPC Group, University of Szeged, Hungary 2Department of Physical Chemistry, University of Szeged, Hungary
3SZTE-MTA Research Group on Supramolecular and Nanostructured Materials, Szeged , Hungary
< http://HPC.inf.hu/>
AbstractThe Alzheimer’s β-amyloid peptide, Aβ, found as aggregated species in Alzheimer’s disease
brain, is linked to the onset of dementia. The toxic properties of Aβ depend on oligomerization and
aggregation. In addition, Aβ toxicity is aggrevated by the presence of zinc ions, which affect the
secondary structure of the peptide. We report the modeling of possible interactions of zinc ions with
Aβ(1-42), one of the most amyloidogenic species known.
The aim of the current study was twofold. First, in order to theoretically handle several Aβ(1-42)
monomers together, a quantum chemical method was sought that is capable of handling peptide systems
comprised of several hundreds residues. Our tests validated the semiempirical parameterization of zinc
termed ZnB, developed by Merz et al. originally for treating zinc metalloenzymes, as capable of
describing complexation of zinc by Aβ(1-42). Used in conjunction with the linear scaling semiempirical
program DivCon („Divide and Conquer”), also by Merz et al., fully quantum chemical treatment of
Aβ(1-42) oligomers and their zinc complexes is possible, requiring only modest computer resources.
The second part of our project considered several possible structures along feasible pathways of
forming proto-aggregate monomers upon complexing zinc with the apo-peptide. DivCon/ZnB
calculations probed putative intermediate conformations, which may play role in the eventual
pathological mis-folding event. Likely participating ligand residues are suggested, besides the histidines
which are the only ones confirmed unequivocally by experiments. Exploring the potential energy
landscape at this novel level of theory provides new structural clues for the process.
Conclusions and outlookConclusions and outlook• We have validated the use of linear scaling ‘We have validated the use of linear scaling ‘DivCon/ZnBDivCon/ZnB’ method of Merz ’ method of Merz et al.et al. for handling zinc for handling zinc metallopeptides.metallopeptides.• The current investigation revealed a novel multi-functional role played by Asp7 in the process of zinc The current investigation revealed a novel multi-functional role played by Asp7 in the process of zinc binding by Aβ.binding by Aβ.• It was demonstrated that this protocol makes feasible a quantum chemical treatment of systems 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 containing hundreds of amino acid residues: on our commodity cluster, typical CPU times for one SCF cycle are well under 1 minute/residue!cycle are well under 1 minute/residue!• This performance will enable studying Aβ aggregates with several monomer units by ‘DivCon/ZnB’;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 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.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 We made, and are releasing, user tools for molecular coordinate processing to streamline work with DivCon format:DivCon format:
<http://Zoli.alturl.com/moletools/>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, ALAP4-00092/2005).
Database structure + calculated protonation
1)1)
Detail of structure, PM3&ZnB optimized
2)2)
3)3)
1) Starting structure is taken from the PDB. An initial 1) Starting structure is taken from the PDB. An initial guess for the protonation state is made with a simple guess for the protonation state is made with a simple Poisson-Boltzmann calculation. This indicated a possibly Poisson-Boltzmann calculation. This indicated a possibly unusual charge for His14, sensitive to the ionic strenght unusual charge for His14, sensitive to the ionic strenght and permittivity of the medium…and permittivity of the medium…
2) The initial crude coordinates are refined by the DivCon 2) The initial crude coordinates are refined by the DivCon routine (implemented in AMBER9), using the ‘ZnB’ routine (implemented in AMBER9), using the ‘ZnB’ reparametrization of the PM3 Hamiltonian. No dielectric reparametrization of the PM3 Hamiltonian. No dielectric is considered at this stage…is considered at this stage…
3) Exploring the micro-hydratation of a putative metal 3) Exploring the micro-hydratation of a putative metal binding region: this is a snapshot of a pocket being binding region: this is a snapshot of a pocket being formed by His6-Asp7-His14. The structure is optimized in formed by His6-Asp7-His14. The structure is optimized in implicit aqueous media (SCRF solvent model), with one implicit aqueous media (SCRF solvent model), with one explicit Hexplicit H22O added…O added…
PM3&ZnB/SCRF optimized
aqueous structure with 2 explicit
waters
4)4)
44) ) Building up the quasi-Building up the quasi-structural water network structural water network within the within the His6-Asp7-His14His6-Asp7-His14 pocket: a second pocket: a second explicit explicit HH22O O is put in. The hydrogen-is put in. The hydrogen-bonding solvent bonding solvent interactions may facilitate interactions may facilitate the arrangement favorable the arrangement favorable for metal binding.for metal binding.
Zinc complexing @ ASP7–HIS14
PM3&ZnB/SCRF optimized aqueous
structure
5)5)
55) ) This is one possible This is one possible arrangement for the initial arrangement for the initial embedding of a Znembedding of a Zn2+2+ ion within ion within the the His6-Asp7-His14His6-Asp7-His14 pocket (for pocket (for simplicity, simplicity, explicit Hexplicit H22O O molecules molecules are not yet inserted here). The are not yet inserted here). The complexing ion can stabilize a complexing ion can stabilize a rearranged structure developing rearranged structure developing subsequently, with a twist of the subsequently, with a twist of the backbone moving the His13 backbone moving the His13 residue into the vicinity of this residue into the vicinity of this region.region.
Zinc complexing @ ASP7–HIS13–HIS14PM3&ZnB/SCRF optimized aqueous structure
6)6)
66) ) In this optimized In this optimized structure a possible structure a possible binding motif for Znbinding motif for Zn2+2+ ion ion is depicted. The is depicted. The arrangement of His13 and arrangement of His13 and His14 coupled by the zinc His14 coupled by the zinc is often considered a is often considered a precondition of precondition of aggregating Aaggregating Aßß. It is . It is interesting to note the interesting to note the unusually active role of unusually active role of Asp7Asp7 in the forming of this in the forming of this complex (while complex (while HisHis6 is 6 is merely a spectator in this merely a spectator in this instance). 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
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
