No New Virus Produced No New Virus Produced New Virus Produced New Virus Produced Ligand Inserted Into Exosite Ligand Inserted Into Exosite HIV Protease Non –Functioning HIV Protease Non –Functioning HIV Protease Functioning HIV Protease Functioning HIV PROTEASE STORY Many AIDS patients can live a normal life when they have the right medication for treating the Human Immunodeficiency Virus - HIV. Sometimes HIV mutates which makes the AIDS patient immune to the medicine they are using. The reason that HIV mutates at a high rate is that the virus is very small and not cellular and so does not have a cellular repair mechanism. Cells have a repair mechanism so that during cellular reproduction changes to the DNA, mutations, which are detected will be rewritten so the new proteins are made correctly. When HIV infects the immune cell it mostly turns off cell processes except for the cell’s ability to make virus proteins. Even though the virus mutates often it must keep enough information to be functional. HIV is a retrovirus which means it has double stranded RNA. It copies its RNA into DNA strands using reverse transcription. Once the HIV has done this, it inserts its DNA into the DNA strand of the host cell. Then the virus can start to make copies of itself using the cell’s machinery. Inside the host, the HIV DNA is transcribed into long strands of messenger RNA and translated into long strings of several proteins. These proteins must be separated so that the proteins can fold up individually into their functional structure. HIV Protease is responsible for the separation of the proteins. Current treatments for HIV are centered around the active site of the enzyme, HIV Protease. These treatments involve insertion of small molecules, ligands, into the active site. When mutations happen in that area of the protease molecule sometimes the current treatment medicines are not able to attach themselves to the active site to stop the production of new viruses. If this happens, AIDS patients get sick again and are not able to fight off infections. New treatments involve putting small molecules, ligands, into another place, an exocite, on the HIV protease molecule to disrupt its functioning. These sites are chosen because they have essential functions that the protease needs to work. The amino acid sequence can not change, mutate, at these sites or no new virus will be produced when the mutant protease is not able to cut the proteins apart. So either way no new viruses are produced. This new treatment will make it possible for current AIDS patients to avoid becoming immune to their medication. This research could be a huge breakthrough for many other diseases. HIV PROTEASE STORY Many AIDS patients can live a normal life when they have the right medication for treating the Human Immunodeficiency Virus - HIV. Sometimes HIV mutates which makes the AIDS patient immune to the medicine they are using. The reason that HIV mutates at a high rate is that the virus is very small and not cellular and so does not have a cellular repair mechanism. Cells have a repair mechanism so that during cellular reproduction changes to the DNA, mutations, which are detected will be rewritten so the new proteins are made correctly. When HIV infects the immune cell it mostly turns off cell processes except for the cell’s ability to make virus proteins. Even though the virus mutates often it must keep enough information to be functional. HIV is a retrovirus which means it has double stranded RNA. It copies its RNA into DNA strands using reverse transcription. Once the HIV has done this, it inserts its DNA into the DNA strand of the host cell. Then the virus can start to make copies of itself using the cell’s machinery. Inside the host, the HIV DNA is transcribed into long strands of messenger RNA and translated into long strings of several proteins. These proteins must be separated so that the proteins can fold up individually into their functional structure. HIV Protease is responsible for the separation of the proteins. Current treatments for HIV are centered around the active site of the enzyme, HIV Protease. These treatments involve insertion of small molecules, ligands, into the active site. When mutations happen in that area of the protease molecule sometimes the current treatment medicines are not able to attach themselves to the active site to stop the production of new viruses. If this happens, AIDS patients get sick again and are not able to fight off infections. New treatments involve putting small molecules, ligands, into another place, an exocite, on the HIV protease molecule to disrupt its functioning. These sites are chosen because they have essential functions that the protease needs to work. The amino acid sequence can not change, mutate, at these sites or no new virus will be produced when the mutant protease is not able to cut the proteins apart. So either way no new viruses are produced. This new treatment will make it possible for current AIDS patients to avoid becoming immune to their medication. This research could be a huge breakthrough for many other diseases. MENTORS Dr. David Stout Determines crystal Structures of a variety of biological macromolecules including HIV protease mutants. Dr. David Goodsell Combines computer graphics and computational chemistry to study the basic mechanisms of protein structure and function. Team Advisor Ann Marie Wellhouse MENTORS Dr. David Stout Determines crystal Structures of a variety of biological macromolecules including HIV protease mutants. Dr. David Goodsell Combines computer graphics and computational chemistry to study the basic mechanisms of protein structure and function. Team Advisor Ann Marie Wellhouse PROCESS OF SCIENCE The SMART Team model will improve our “ability to visualize the 'exosite', a surface cleft in HIV Protease, that will aid our drug design efforts, i.e. the discovery of small molecules that bind specifically in this cleft,” (Dr. David Stout, 2009, personal communication). “The colored space filling models the students are generating” at the exocite and separate ligands, “will help a lot. I'm sure I will refer to this model often,” (Stout, 2009). PROCESS OF SCIENCE The SMART Team model will improve our “ability to visualize the 'exosite', a surface cleft in HIV Protease, that will aid our drug design efforts, i.e. the discovery of small molecules that bind specifically in this cleft,” (Dr. David Stout, 2009, personal communication). “The colored space filling models the students are generating” at the exocite and separate ligands, “will help a lot. I'm sure I will refer to this model often,” (Stout, 2009). METHODS The physical models were produced On a Z Corp printer. Z Corporation printers produce handheld color models. Our team used RasMol to design the model and it was printed in Dr. Arthur Olsen’s Lab. The poster was printed at the San Diego Super Computer Center. METHODS The physical models were produced On a Z Corp printer. Z Corporation printers produce handheld color models. Our team used RasMol to design the model and it was printed in Dr. Arthur Olsen’s Lab. The poster was printed at the San Diego Super Computer Center. SPECIAL THANKS We would like to thank: Our Mentors, advisor and teachers; Dr. Art Olson for printing our model; Marisela Chevez from The Scripps Research Institute; Ange Mason, Dr. Diane Baxter and Jeff Sale at the San Diego Super Computer Center for supporting our project; The Howard Hughes Medical Institute and the Center for Biomolecular Modeling at the Milwaukee School of Engineering for funding our project. SMART TEAM Jerry Ruiz Marcial Longworth Edwin Escobar Alfred Johnson Abdulazee Anifowoshi Diana Townsend Arroyo Paseo Charter High School 4001 El Cajon Blvd., Suite 205 San Diego, CA SMART TEAM Jerry Ruiz Marcial Longworth Edwin Escobar Alfred Johnson Abdulazee Anifowoshi Diana Townsend Arroyo Paseo Charter High School 4001 El Cajon Blvd., Suite 205 San Diego, CA T-Cell SUMMARY HIV protease is a vital protein of the HIV virus. The protease cuts apart the proteins that must fold into their functional shape so that new viruses can be made. If the medicine attaches to the exosite then the HIV protease is unable to function. This research will hopefully make it possible for current AIDS patients to be just as healthy as they were before the AIDS virus infected them. SUMMARY HIV protease is a vital protein of the HIV virus. The protease cuts apart the proteins that must fold into their functional shape so that new viruses can be made. If the medicine attaches to the exosite then the HIV protease is unable to function. This research will hopefully make it possible for current AIDS patients to be just as healthy as they were before the AIDS virus infected them. HIV REFERENCES Structure of HIV Protease from the Protein Data Bank (PDB) from the net: pdb.org/pdb/explore/explore_do ?structureld=2AZC Structure of HIV from the net: nlyres/639C00 Image of an artery from the net: spectrum-health.org X-ray image of human veins from the net: w1.siemens.com REFERENCES Structure of HIV Protease from the Protein Data Bank (PDB) from the net: pdb.org/pdb/explore/explore_do ?structureld=2AZC Structure of HIV from the net: nlyres/639C00 Image of an artery from the net: spectrum-health.org X-ray image of human veins from the net: w1.siemens.com Separated Proteins Fold Separated Proteins Fold INTRODUCTION HIV (Human Immunodeficiency Virus) attacks and destroys the blood cells CD4 and T-cells, which will lead to AIDS. HIV kills millions of people and has been declared a Pandemic. Finding a cure would provide a better life to people all around the world, especially in Africa which has been hit the hardest, and could lower the cost of health care. Dr. David Stout is a crystallographer who studies protein structure as a way to help find a cure. In his research Dr. Stout looks around the structure of HIV Protease to find where the medicine can function to disrupt the development of the viruses after initial infection of the immune system to stop the growth and development of the disease. INTRODUCTION HIV (Human Immunodeficiency Virus) attacks and destroys the blood cells CD4 and T-cells, which will lead to AIDS. HIV kills millions of people and has been declared a Pandemic. Finding a cure would provide a better life to people all around the world, especially in Africa which has been hit the hardest, and could lower the cost of health care. Dr. David Stout is a crystallographer who studies protein structure as a way to help find a cure. In his research Dr. Stout looks around the structure of HIV Protease to find where the medicine can function to disrupt the development of the viruses after initial infection of the immune system to stop the growth and development of the disease.