GROMACS appears to be able to perform coarse-grained (CG) lipid MD simulation (CG is simplified lipid representation model). Some dudes use this representation to reveal membrane-bound protein orientation relative to lipid bilayer. Results were refined with atomistic MD to obtain more detailed info.
src
Wednesday, August 26, 2009
Tuesday, August 25, 2009
Analysis of disease-related polypeptide sequences: Intrinsically unstructured proteins
Analysis of disease-related polypeptide sequences: Intrinsically unstructured proteins
Amyloid-β-protein
The most abundant forms found in amyloid plaques are a 40-mer (Aβ40) and a 42-mer (Aβ42). Although less abundant, Aβ42 is more amyloidogenic than Aβ40 and is the major component of neuritic plaques. Two main regions with high aggregation propensity can be distinguished in the aggregation profile for this polypeptide. The second region arises from the contribution of two sequence stretches comprising residues 30–36 and 38–42, respectively.
key residues: 16-21 (located in the core of Aβ fibrils)
A short 7 residues fragment comprising residues 16–22 is able to form ordered amyloid fibrils and, more interestingly, 16-LVAFF-20 and derived peptides have been shown to bind to Aβ42 and act as potent inhibitors of amyloid formation.
Islet amyloid polypeptide
Beta-cell failure in type II diabetes correlates with the formation of pancreatic islet amyloid. Islet amyloid polypeptide (IAPP, amylin), the major component of islet amyloid, is co-secreted with insulin from beta-cells.
In type II diabetes, this peptide aggregates to form amyloid fibrils that are toxic to beta-cells [26]. IAPP is an unstructured peptide hormone of 37 amino acid residues. Two "hot spots" of aggregation comprising residues 12–18 and 22–28 are detected for this peptide.
Interestingly enough, a 8–37 IAPP-fragment including both "hot spots", has been shown to form amyloid fibrils under physiological conditions.
Residues 12–17 and 22–27 are proposed to form the inner β-sheets in the fibril protofilament structure. According to this hypothesis, peptides corresponding to residues 8–20, 10–19, 20–29 of human IAPP, which include one of the "hot spots" described here, all form amyloid.
Smaller peptides derived from these regions have also been shown to form amyloid, and a recent investigation suggests that the minimal amyloid forming fragment of IAPP consists of residues 22–27. This hexapeptide fragment, NFGAIL, forms β-sheet-containing fibrils that coil around each other in typical amyloid fibril morphology.
proposed mechanisms:
- increased production and secretion of IAPP associated with increased demand for insulin might result in accumulation and aggregation of IAPP.
- impaired processing of the IAPP precursor molecule, proIAPP, by islet betacells may lead to hypersecretion of unprocessed or partially processed forms of proIAPP that may have a higher tendency for aggregation compared to mature IAPP
α-Synuclein
Several large aggregation-prone stretches were predicted for the α-Synuclein sequence: region 1–18, region 27–56 and specially region 61–94. A peptide comprising residues 68–78 of α-synuclein has been shown to be the minimum fragment that, like α-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. This fragment is included in the region 62–80 which we predict as the sequence stretch with the highest aggregation propensity. All the α-synucleinopathies are characterized by the accumulation of the 35 residues NAC fragment in the insoluble deposits. [NAC= non-Aβ component, amino acids 61–95]
(src)
Amyloid-β-protein
The most abundant forms found in amyloid plaques are a 40-mer (Aβ40) and a 42-mer (Aβ42). Although less abundant, Aβ42 is more amyloidogenic than Aβ40 and is the major component of neuritic plaques. Two main regions with high aggregation propensity can be distinguished in the aggregation profile for this polypeptide. The second region arises from the contribution of two sequence stretches comprising residues 30–36 and 38–42, respectively.
key residues: 16-21 (located in the core of Aβ fibrils)
A short 7 residues fragment comprising residues 16–22 is able to form ordered amyloid fibrils and, more interestingly, 16-LVAFF-20 and derived peptides have been shown to bind to Aβ42 and act as potent inhibitors of amyloid formation.
Islet amyloid polypeptide
Beta-cell failure in type II diabetes correlates with the formation of pancreatic islet amyloid. Islet amyloid polypeptide (IAPP, amylin), the major component of islet amyloid, is co-secreted with insulin from beta-cells.
In type II diabetes, this peptide aggregates to form amyloid fibrils that are toxic to beta-cells [26]. IAPP is an unstructured peptide hormone of 37 amino acid residues. Two "hot spots" of aggregation comprising residues 12–18 and 22–28 are detected for this peptide.
Interestingly enough, a 8–37 IAPP-fragment including both "hot spots", has been shown to form amyloid fibrils under physiological conditions.
Residues 12–17 and 22–27 are proposed to form the inner β-sheets in the fibril protofilament structure. According to this hypothesis, peptides corresponding to residues 8–20, 10–19, 20–29 of human IAPP, which include one of the "hot spots" described here, all form amyloid.
Smaller peptides derived from these regions have also been shown to form amyloid, and a recent investigation suggests that the minimal amyloid forming fragment of IAPP consists of residues 22–27. This hexapeptide fragment, NFGAIL, forms β-sheet-containing fibrils that coil around each other in typical amyloid fibril morphology.
proposed mechanisms:
- increased production and secretion of IAPP associated with increased demand for insulin might result in accumulation and aggregation of IAPP.
- impaired processing of the IAPP precursor molecule, proIAPP, by islet betacells may lead to hypersecretion of unprocessed or partially processed forms of proIAPP that may have a higher tendency for aggregation compared to mature IAPP
α-Synuclein
Several large aggregation-prone stretches were predicted for the α-Synuclein sequence: region 1–18, region 27–56 and specially region 61–94. A peptide comprising residues 68–78 of α-synuclein has been shown to be the minimum fragment that, like α-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. This fragment is included in the region 62–80 which we predict as the sequence stretch with the highest aggregation propensity. All the α-synucleinopathies are characterized by the accumulation of the 35 residues NAC fragment in the insoluble deposits. [NAC= non-Aβ component, amino acids 61–95]
(src)
Thursday, August 20, 2009
transmembrane protein modeling pt. 3
After several days of brainfucking the following system was obtained:
The membrane protein metodology, described on Bevan Lab site, recommends to perform an NVT (constant: particles number, volume and temperature) equilibration. But due to unknown reason the membrane separates into two layers looking like a sandwich (process takes 0.38 ps).
Solution: using lipid pos. restraints in z-dimension + simulated annealing 0..315 (310 is phase transition temperature for POPC) + NPT (constant number, pressure, temp.) ensemble conditions.
The membrane protein metodology, described on Bevan Lab site, recommends to perform an NVT (constant: particles number, volume and temperature) equilibration. But due to unknown reason the membrane separates into two layers looking like a sandwich (process takes 0.38 ps).
Solution: using lipid pos. restraints in z-dimension + simulated annealing 0..315 (310 is phase transition temperature for POPC) + NPT (constant number, pressure, temp.) ensemble conditions.
Wednesday, August 19, 2009
transmembrane protein modeling pt. 2
Protein-lipid_bilayer system generated with Schroedinger`s Desmond gives too large bilayer hole, which can contain water molecules after solvation. Some manuals recommended to make a local vdwradii.dat copy with modified C radius (0.5 [0.15 is default]). But 0.5 appears to be not enough (0.6 was used).
The Desmond Membrane Builder fuckup lies in fact that I can manually implement protein into membrane more accurately, but having more brainfucking post-processing. So it goes.
The Desmond Membrane Builder fuckup lies in fact that I can manually implement protein into membrane more accurately, but having more brainfucking post-processing. So it goes.
transmembrane protein modeling
Lipid topology (.itp required for GROMACS MD simulations) contains 52 atoms. But lipid bilayer PDB structure consists of (>52)-atom molecules (such a difference is a result of using united-atom force field) with all hydrogens, which were considered in GROMOS96 53a6 FF. It was obtained 52-atom molecules system with:
cat lipid.pdb | grep -v "0.00 H" > lipid-noH.pdb
Output PDB format details depends on software:
mdrun -deffnm box-min -c box-min.pdb -v -nice 0 # output is box-min.pdb [box-min.tpr assumed to be exist]
mdrun -deffnm box-min -c box-min.gro -v -nice 0 # output is box-min.gro
vmd box-min.gro # box-min.gro was converted to box-min(from_gro).pdb with vmd
spdbv box-min.pdb # warning 1: at least one HETATM group lacked proper CONNECT informations. Connection will be generated between atoms that are closer than 2.000A, which can generate false bonds. [CONNECT section was removed manually] warning 2: File ignored (either or is not a valid PDB file, or it contains only a Carbon Alpha trace). => spdbv doesn`t understand GROMACS PDB output
spdbv box-min(from_gro).pdb #warning 1: the same; => successfully opened
cat lipid.pdb | grep -v "0.00 H" > lipid-noH.pdb
Output PDB format details depends on software:
mdrun -deffnm box-min -c box-min.pdb -v -nice 0 # output is box-min.pdb [box-min.tpr assumed to be exist]
mdrun -deffnm box-min -c box-min.gro -v -nice 0 # output is box-min.gro
vmd box-min.gro # box-min.gro was converted to box-min(from_gro).pdb with vmd
spdbv box-min.pdb # warning 1: at least one HETATM group lacked proper CONNECT informations. Connection will be generated between atoms that are closer than 2.000A, which can generate false bonds. [CONNECT section was removed manually] warning 2: File ignored (either or is not a valid PDB file, or it contains only a Carbon Alpha trace). => spdbv doesn`t understand GROMACS PDB output
spdbv box-min(from_gro).pdb #warning 1: the same; => successfully opened
Wednesday, August 12, 2009
MAPAS
It’s All About Geometry: Protein Contact Surfaces Hold Key to Cures
Server for protein-membrane contact points is described.
MAPAS Membrane-Associated Protein Assessments
http://cancer-tools.sdsc.edu/MAPAS/pro2.html
Server for protein-membrane contact points is described.
MAPAS Membrane-Associated Protein Assessments
http://cancer-tools.sdsc.edu/MAPAS/pro2.html
Tuesday, August 11, 2009
protein aggregation
0) http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1828741&blobtype=pdf&tool=pmcentrez
AGGRESCAN: a server for the prediction and evaluation of "hot spots" of aggregation in polypeptides
Aggrescan.
AGGRESCAN: a server for the prediction and evaluation of "hot spots" of aggregation in polypeptides
Aggrescan.
transmembrane proteins
0) http://www.iop.org/EJ/abstract/0953-8984/18/28/S07
Membrane protein simulations with a united-atom lipid and all-atom protein model: lipid–protein interactions, side chain transfer free energies and model proteins
Arguments on using combination of OPLS and united-atom force field in GROMACS.
1) http://mccammon.ucsd.edu/~rlaw/ctbp_workshop_rlaw.htm
Explicit Membrane Protein Simulations in NAMD/VMD
Transmembrane protein modeling manual. Human glycophorin (1AFO) made with NAMD software.
Membrane protein simulations with a united-atom lipid and all-atom protein model: lipid–protein interactions, side chain transfer free energies and model proteins
Arguments on using combination of OPLS and united-atom force field in GROMACS.
1) http://mccammon.ucsd.edu/~
Explicit Membrane Protein Simulations in NAMD/VMD
Transmembrane protein modeling manual. Human glycophorin (1AFO) made with NAMD software.
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