Sandbox 250: Difference between revisions

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==='''Introduction'''===

Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh), and therefore the termination of the nerve impulse in cholinergic synapses. Irreversible inhibition of AChE can lead to increased levels of ACh in cholinergic synapses and ultimately death. Conversely, suppressed levels of ACh may lead to memory deficits associated with Alzheimer's disease. AChE has a deep(20Å) and narrow(5Å) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge. Initially, ACh binds to the peripheral anionic site(PAS) of AChE and is funneled down the gorge to the active site by interactions between the aromatic rings of the 14 aromatic residues and the quaternary ammonium ion of ACh. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic ion site and the quaternary ammonium ion of ACh. The Fasciculin-II (FAS-II)toxin, a component of the East African Green Mamba snake(''Dendroaspis angusticeps'') venom, inhibits AChE by binding to the top of the active-site gorge, including residues that form the PAS; thus preventing ACh from entering the active-site gorge. The Hostos-Lincoln Academy Students Modeling A Research Topic(S.M.A.R.T) team and the Center for BioMolecular Modeling have designed and fabricated two physical models using a combination of computational molecular modeling and three-dimensional(3D) printing technology: ''Torpedo californica''(''Tc'') AChE in complex with a modeled ACh ligand and ''Tc''AChE in complex with FAS-II.

Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh)(Figure 1), and therefore the termination of the nerve impulse in cholinergic synapses(Figure 2). Irreversible inhibition of AChE can lead to increased levels of ACh in cholinergic synapses and ultimately death. Conversely, suppressed levels of ACh may lead to memory deficits associated with Alzheimer's disease. AChE has a deep(20Å) and narrow(5Å) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge. Initially, ACh binds to the peripheral anionic site(PAS) of AChE and is funneled down the gorge to the active site by interactions between the aromatic rings of the 14 aromatic residues and the quaternary ammonium ion of ACh. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic ion site and the quaternary ammonium ion of ACh. The Fasciculin-II (FAS-II)toxin, a component of the East African Green Mamba snake(''Dendroaspis angusticeps'') venom, inhibits AChE by binding to the top of the active-site gorge, including residues that form the PAS; thus preventing ACh from entering the active-site gorge. The Hostos-Lincoln Academy Students Modeling A Research Topic(S.M.A.R.T) team and the Center for BioMolecular Modeling have designed and fabricated two physical models using a combination of computational molecular modeling and three-dimensional(3D) printing technology: ''Torpedo californica''(''Tc'') AChE in complex with a modeled ACh ligand and ''Tc''AChE in complex with FAS-II.

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The ''Tc''<scene name='Sandbox_250/Ache_ach/5'>AChE</scene> protein contains 537 amino acids and forms an α/β hydrolase fold. The neurotransmitter <scene name='Sandbox_250/Ache_ach/36'>ACh</scene> consists of an acytoxy group, an ethylene group and a positively charged quaternary ammonium ion.

The <scene name='Sandbox_250/Ache_ach/24'>14 aromatic residues</scene> that line the active site gorge are Tyr70, Trp84, Trp120, Tyr121, Tyr130, Trp233, Trp279, Phe288, Phe290, Phe330, Phe331, Tyr334, Trp432 and Tyr442. These aromatic residues interact with the positively charged quaternary ammonium ion of ACh by virtue of cation-π interactions to filter it down the active-site gorge to the catalytic triad.

The <scene name='Sandbox_250/Ache_ach/24'>14 aromatic residues</scene> that line the active site gorge are Tyr70, Trp84, Trp120, Tyr121, Tyr130, Trp233, Trp279, Phe288, Phe290, Phe330, Phe331, Tyr334, Trp432 and Tyr442. These aromatic residues interact with the positively charged quaternary ammonium ion of ACh by virtue of cation-π interactions to filter it down the active-site gorge to the catalytic triad (Figure 3).

The PAS includes residues <scene name='Sandbox_250/Ache_ach/11'>Tyr70, Tyr121 and Trp279</scene>. Initially, the positively charged quaternary ammonium ion of ACh is attracted to and binds to the <scene name='Sandbox_250/Ache_ach/31'>PAS of AChE</scene>, highlighted in yellow.

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FAS-II binds to and inhibits AChE using two major mechanisms:

1. Long-range electrostatic complementarity: the positive lower region of FAS-II is attracted to the highly negative top region of AChE.

1. Long-range electrostatic complementarity: the positive lower region of FAS-II is attracted to the highly negative top region of AChE (Figure 4).

2. Amino acid specificity: residues <scene name='Sandbox_250/Ache_fas2/14'>Thr8, Arg27 and Met33</scene> are located on two of the three fingers of FAS-II. When FAS-II <scene name='Sandbox_250/Ache_fas2/18'>binds</scene> to AChE, Arg27 and Met33 interact with Trp279 part of the PAS, while Thr8 and Val34 interact with Tyr70, also part of the PAS.

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@@ Line 10: / Line 10: @@
 ==='''Introduction'''===
-Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh), and therefore the termination of the nerve impulse in cholinergic synapses. Irreversible inhibition of AChE can lead to increased levels of ACh in cholinergic synapses and ultimately death. Conversely, suppressed levels of ACh may lead to memory deficits associated with Alzheimer's disease. AChE has a deep(20Å) and narrow(5Å) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge. Initially, ACh binds to the peripheral anionic site(PAS)  of AChE and is funneled down the gorge to the active site by interactions between the aromatic rings of the 14 aromatic residues and the quaternary ammonium ion of ACh. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic ion site and the quaternary ammonium ion of ACh. The Fasciculin-II (FAS-II)toxin, a component of the East African Green Mamba snake(''Dendroaspis angusticeps'') venom, inhibits AChE by binding to the top of the active-site gorge, including residues that form the PAS; thus preventing ACh from entering the active-site gorge. The Hostos-Lincoln Academy Students Modeling A Research Topic(S.M.A.R.T) team and the Center for BioMolecular Modeling have designed and fabricated two physical models using a combination of computational molecular modeling and three-dimensional(3D) printing technology: ''Torpedo californica''(''Tc'') AChE in complex with a modeled ACh ligand and ''Tc''AChE in complex with FAS-II.
+Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh)(Figure 1), and therefore the termination of the nerve impulse in cholinergic synapses(Figure 2). Irreversible inhibition of AChE can lead to increased levels of ACh in cholinergic synapses and ultimately death. Conversely, suppressed levels of ACh may lead to memory deficits associated with Alzheimer's disease. AChE has a deep(20Å) and narrow(5Å) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge. Initially, ACh binds to the peripheral anionic site(PAS)  of AChE and is funneled down the gorge to the active site by interactions between the aromatic rings of the 14 aromatic residues and the quaternary ammonium ion of ACh. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic ion site and the quaternary ammonium ion of ACh. The Fasciculin-II (FAS-II)toxin, a component of the East African Green Mamba snake(''Dendroaspis angusticeps'') venom, inhibits AChE by binding to the top of the active-site gorge, including residues that form the PAS; thus preventing ACh from entering the active-site gorge. The Hostos-Lincoln Academy Students Modeling A Research Topic(S.M.A.R.T) team and the Center for BioMolecular Modeling have designed and fabricated two physical models using a combination of computational molecular modeling and three-dimensional(3D) printing technology: ''Torpedo californica''(''Tc'') AChE in complex with a modeled ACh ligand and ''Tc''AChE in complex with FAS-II.
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@@ Line 53: / Line 53: @@
 The ''Tc''<scene name='Sandbox_250/Ache_ach/5'>AChE</scene> protein contains 537 amino acids and forms an α/β hydrolase fold. The neurotransmitter <scene name='Sandbox_250/Ache_ach/36'>ACh</scene> consists of an acytoxy group, an ethylene group and a positively charged quaternary ammonium ion.
-The <scene name='Sandbox_250/Ache_ach/24'>14 aromatic residues</scene> that line the active site gorge are Tyr70, Trp84, Trp120, Tyr121, Tyr130, Trp233, Trp279, Phe288, Phe290, Phe330, Phe331, Tyr334, Trp432 and Tyr442. These aromatic residues interact with the positively charged quaternary ammonium ion of ACh by virtue of cation-π interactions to filter it down the active-site gorge to the catalytic triad.
+The <scene name='Sandbox_250/Ache_ach/24'>14 aromatic residues</scene> that line the active site gorge are Tyr70, Trp84, Trp120, Tyr121, Tyr130, Trp233, Trp279, Phe288, Phe290, Phe330, Phe331, Tyr334, Trp432 and Tyr442. These aromatic residues interact with the positively charged quaternary ammonium ion of ACh by virtue of cation-π interactions to filter it down the active-site gorge to the catalytic triad (Figure 3).
 The PAS includes residues <scene name='Sandbox_250/Ache_ach/11'>Tyr70, Tyr121 and Trp279</scene>. Initially, the positively charged quaternary ammonium ion of ACh is attracted to and binds to the <scene name='Sandbox_250/Ache_ach/31'>PAS of AChE</scene>, highlighted in yellow.
@@ Line 74: / Line 74: @@
 FAS-II binds to and inhibits AChE using two major mechanisms:
-. Long-range electrostatic complementarity: the positive lower region of FAS-II is attracted to the highly negative top region of AChE.
+. Long-range electrostatic complementarity: the positive lower region of FAS-II is attracted to the highly negative top region of AChE (Figure 4).
 . Amino acid specificity: residues <scene name='Sandbox_250/Ache_fas2/14'>Thr8, Arg27 and Met33</scene> are located on two of the three fingers of FAS-II. When FAS-II <scene name='Sandbox_250/Ache_fas2/18'>binds</scene> to AChE, Arg27 and Met33 interact with Trp279 part of the PAS, while Thr8 and Val34 interact with Tyr70, also part of the PAS.