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=='''Physical Models of Acetylcholinesterase in Complex with Acetylcholine and the Green Mamba Snake Toxin, Fasciculin-II'''==
=='''Acetylcholinesterase:  A Story of Substrate Traffic and Inhibition'''==
Students: Mary Acheampong. Daviana Dueño, Bobby Glover, Alafia Henry, Randol Mata, and Marisa VanBrakle, Hostos-Lincoln Academy.
Students: Mary Acheampong. Daviana Dueño, Bobby Glover, Alafia Henry, Randol Mata, and Marisa VanBrakle, Hostos-Lincoln Academy.


Teacher: Allison Granberry, Hostos-Lincoln Academy
Teacher: Allison Granberry, Hostos-Lincoln Academy


Mentors: Joel Sussman, Weissman Institute of Science, and Lars Westblade, Touro College of Pharmacy.
Mentors: Joel L. Sussman, Weizmann Institute of Science, and Lars Westblade, Touro College of Pharmacy.
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==='''Introduction'''===
==='''Introduction'''===


Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh), 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 <ref>PMID: 14501022</ref>. AChE has a deep(20Å) and narrow(5Å) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge<ref>PMID: 1678899</ref>. 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<ref>PMID:8747462</ref>. 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 hydrolysis of the neurotransmitter acetylcholine (ACh), and, therefore, for termination of impulse transmission at cholinergic synapses (Figure 2). Irreversible inhibition of AChE can result in accumulation of ACh at cholinergic synapses and, ultimately, to death. Conversely, decreased levels of ACh may result in the memory deficits associated with Alzheimer's disease<ref>PMID: 14501022</ref>. AChE has a deep (20Å) and narrow (5Å) gorge lined with 14 aromatic residues, with its active site located near the bottom of the gorge<ref>PMID: 1678899</ref>. Initially, ACh binds to the peripheral anionic site (PAS) of AChE, and is funneled down the gorge to the active site by interactions between its quaternary ammonium group and the aromatic rings of 14 aromatic amino acid residues lining the gorge. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic site and its quaternary ammonium group. Fasciculin-II (FAS-II), a potent polypeptide toxin present in the venom of the East African green mamba (Dendroaspis angusticeps), inhibits AChE by binding to the top of the active-site gorge, interacting tightly with residues that form the PAS; it thus prevents ACh from entering the active-site gorge<ref>PMID:8747462</ref>. 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 complexed with a modeled ACh molecule ligand, and a complex of FAS-II with ''Tc''AChE.
 
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==='''Background Information'''===
==='''Background Information'''===
[[Image:AChE-Page-Cholinergic-Synapse.jpg|thumb|alt= Alt text| Figure 2. Cholinergic Synapse |375px]]


When a nerve impulse reaches the presynaptic nerve terminal of a cholinergic synpase, it stimulates the release of the neurotransmitter, ACh (Figure 1), into the synaptic cleft. ACh diffuses across the cleft to the postsynaptic nerve terminal, where it binds reversibly to acetylcholine receptors embedded in the membrane of the postsynaptic nerve terminal. The binding of ACh to the receptors triggers a nerve impulse in the postsynaptic neuron. Finally AChE, anchored to the membrane of the postsynaptic nerve terminal (Figure 2), hydrolyzes ACh to acetate and choline, resulting in the termination of neurotransmission.
[[Image:AChE-Page-ACh_shematic.JPG|left|thumb|alt= Alt text| Figure 1. Chemical Structure of Acetylcholine |275px]]


 
Inhibition of AChE may result in various outcomes, depending on the physiological context. Toxins such as FAS-II, from the green mamba, a poisonous snake found in East Africa, inhibit AChE and ultimately lead to death. However, controlled inhibition of AChE, in patients with Alzheimer’s disease, by drugs designed for this purpose, alleviates  their symptoms, including memory loss and disorientation.
[[Image:AChE-Page-Cholinergic-Synapse.jpg|thumb|alt= Alt text| Figure 2. Cholernergic Synapse |375px]]
 
 
When a nerve impulse reaches the presynaptic nerve terminal, where it stimulates the release of the neurotransmitter, ACh(Figure 1), into the cholinergic synapse. ACh diffuses across the synapse to the postsynaptic nerve terminal, and binds to receptors embedded in the membrane of the  postsynaptic nerve terminal. The binding of ACh to receptors in the postsynaptic neuron re-initiates the nerve impulse. Finally AChE, anchored to the membrane of the postsynaptic nerve terminal(Figure 2), hydrolyzes ACh to acetate and choline resulting in the termination of the nerve  impulse at the synapse.
[[Image:AChE-Page-ACh_shematic.JPG|left|thumb|alt= Alt text| Figure 1. Chemical Structure of Acetylcholine |275px]]
Inhibition of AChE may result in different outcomes, depending on the physiological context. Toxins such as FAS-II from the East African Green Mamba snake inhibit AChE and ultimately lead to death. Conversely, reversible inhibition of AChE, in patients with Alzheimer’s disease, is an effective way to improve their symptoms, including memory loss and disorientation.


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3. Shape: Once bound to the PAS, two loops of FAS-II fit in to the AChE active-site gorge like a hand fits into a glove. Once this occurs, the entrance of the gorge is <scene name='Sandbox_250/Ache_fas2/13'>blocked</scene> such that acetylcholine may not enter, and therefore it will not be hydrolysed. This results in the increased levels of AChE in the cholinergic synapse, and ultimately death.
3. Shape: Once bound to the PAS, two loops of FAS-II fit in to the AChE active-site gorge like a hand fits into a glove. Once this occurs, the entrance of the gorge is <scene name='Sandbox_250/Ache_fas2/13'>blocked</scene> such that acetylcholine may not enter, and therefore it will not be hydrolysed. This results in the increased levels of AChE in the cholinergic synapse, and ultimately death.


[[Image:New_Schematic_AChE_Fas.JPG|left|thumb|alt= Alt text| Figure 4. AChE-fasciculin-2 complex. (a) A side view of the complex, illustrating the geometric complementarity of the two interacting proteins. AChE is presented as a yellow surface and fasciculin-2 as a blues ribbon. (b) A front view of both interacting proteins, presented separately as surfaces colored by electrostatic potential (blue is positive, white is neutral, and red is negative). To create this view, both proteins were rotated 90º compared to their position in a, AChE to the right and fasciculin to the left. The electrostatic compatibility between the two proteins is clear; The positively charged part of fasciculin matches the entrance to AChE's binding site, which is negatively charged.|500px]]
[[Image:New_Schematic_AChE_Fas.JPG|left|thumb|alt= Alt text| Figure 4. AChE-fasciculin-2 complex. (a) A side view of the complex, illustrating the geometric complementarity of the two interacting proteins. AChE is presented as a yellow surface and fasciculin-2 as a blues ribbon. (b) A front view of both interacting proteins, presented separately as surfaces colored by electrostatic potential (blue is positive, white is neutral, and red is negative). To create this view, both proteins were rotated 90º compared to their position in a, AChE to the right and fasciculin to the left. The electrostatic compatibility between the two proteins is clear; The positively charged part of fasciculin matches the entrance to AChE's binding site, which is negatively charged <ref>Kessel A and Ben-Tal N (Dec. 2010) Introduction to Proteins: Structure, Function, and Motion. Chapman & Hall/CRC Mathematical & Computational Biology. ISBN: 9781439810712</ref>.|500px]]


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==='''References'''===
==='''References'''===
<references/>
<references/>
5. Amit Kessel and Nir Ben-Tal (Dec. 2010) Introduction to Proteins: Structure, Function, and Motion. Chapman & Hall/CRC Mathematical & Computational Biology. ISBN: 9781439810712


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7. Michal Harel, Weizmann Institute of Science
7. Michal Harel, Weizmann Institute of Science


8. Hostos Community College, Bronx, NY
8. Natural Sciences Department,Hostos Community College, Bronx, NY


9. Malcolm Twist
9. Malcolm Twist

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