Thomas E Cheatham
University Of Utah
Project start date: 2008-02-01
Project end date: 2013-01-31
Sponsored Links Excellgen http://Excellgen.com
BIOMOLECULAR SIMULATION FOR THE END-STAGE REFINEMENT OF NUCLEIC ACID STRUCTURE
Thomas E Cheatham, Associate Professor
University Of Utah, 75 South 2000 East, Salt Lake City, Ut 84112
Grant 5R01GM081411-03 from National Institute Of General Medical Sciences
Abstract: Biomolecular simulation for the end-stage refinement of nucleic acid structure The structure, dynamics, and interactions of nucleic acids are fundamental to their function. Our aim is to utilized advanced atomistic simulation methods to perform the "end-stage" refinement of nucleic acid structure with a specific focus on RNA structure, function and drug targeting. To do this, we will refine empirical force fields for representing nucleic acid structure, explore the dynamics (including bendability, twistability and alteration of the properties by the environment of water, salt, proteins and other interacting ligands), and assess the performance on representative model structure. Our integrated set of hypothesis are that Using improved empirical force fields and improved molecular dynamics and free energy simulation protocols (including enhanced sampling methods), we can (1) perform the "end-stage" refinement and ranking of putative RNA model structures and (2) better understand the interaction of putative drugs with nucleic acids. Moreover, (3) by making datasets and analyses of large sets of MD trajectories of varied nucleic acids generally available, the community will move forward faster in understanding the strengths, limitations, and uses of MD data for representing nucleic acid structure, dynamics, and interaction at multiple scales. It is our aim to refine and rank the relative importance of putative RNA models. In other words, given putative three-dimensional RNA models that satisfy secondary structure restraints, we believe that we can use simulation to move closer to the correct atomic structure and that we can rank the relative importance or reliability of a given model. Applications, beyond a large set of common and representative DNA and RNA structure motifs, include a study of codon-anticodon interactions in the model system of hypermodified tRNAlys interacting with the HIV1-A loop (important for initiation of the virus), optimizing RNA bulged targeting drugs, and detailed characterization of sequence specific structure and dynamics in DNA minicircles and nucleosome positioning sequences. Such studies, beyond providing fundamental insight into nucleic acid structure and dynamics, provide a basis for the development of computer-aided- drug-design strategies for targeting nucleic acid structure (in applications ranging from cancer to antibiotics) and will demonstrate the important role biomolecular simulations can play in deciphering nucleic acid structure / function relationships. Using advanced atomistic simulation methods we will perform the "end-stage" refinement of nucleic acid structure with a specific focus on RNA structure, function and drug targeting and explore a novel data dissemination model where our raw simulation results are made available to the larger community. Such studies, beyond providing fundamental insight into nucleic acid structure and dynamics, provide a basis for the development of computer-aided-drug-design strategies for targeting nucleic acid structure (in applications ranging from cancer to antibiotics) and will demonstrate the important role biomolecular simulations can play in deciphering nucleic acid structure / function relationships
Keywords: Amber; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Anticodon; Biological Models; Budgets; Burn injury; Burns; Cancers; Cells; Codon; Codon Nucleotides; Collaborations; Coloring Agents; Communities; Computer Assisted; Computer Hardware; Computers; Critiques; DNA; Data; Data Set; Dataset; Deoxyribonucleic Acid; Development; Drug Delivery; Drug Delivery Systems; Drug Design; Drug Targeting; Drug Targetings; Drugs; Dyes; Free Energy; Gene Products, RNA; Goals; Hour; Hydrogen Oxide; Investigation; Ions; Ligands; Malignant Neoplasms; Malignant Tumor; Medication; Memory; Methods; Miscellaneous Antibiotic; Model System; Modeling; Models, Biologic; Molecular Dynamics Simulation; Nucleic Acids; Nucleosomes; Peptides; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Play; Position; Positioning Attribute; Property; Property, LOINC Axis 2; Protein Binding; Proteins; Protocol; Protocols documentation; RNA; RNA, Non-Polyadenylated; Relative; Relative (related person); Research Design; Ribonucleic Acid; Right-On; Role; Running; Sampling; Solutions; Spinal Column; Spine; Staging; Structure; Structure-Activity Relationship; Students; Study Type; System; System, LOINC Axis 4; Testing; Thermodynamic; Thermodynamics; Time; Utah; Validation; Vertebral column; Virus; Viruses, General; Water; backbone; base; chemical structure function; computer aided; computer system hardware; cost; drug/agent; experiment; experimental research; experimental study; gene product; improved; insight; interest; malignancy; molecular dynamics; nano second; nanosecond; neoplasm/cancer; novel; nucleic acid structure; research study; response; restraint; salt water environment; saltwater environment; simulation; social role; structure function relationship; study design
Project start date: 2008-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01GM081411-03 (2010): $297990
Grants awarded to Thomas E Cheatham
INSIGHT INTO BIOMOLECULAR STRUCTURE, DYNAMICS, INTERACTIONS AND ENERGETIC FROM
Thomas E Cheatham
Carnegie-mellon University, 5000 Forbes Ave, Pittsburgh, Pa 15213
Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aim of our continuing studies is to push the boundaries of atomistic biomolecular simulation methods with a goal to expose deficiencies in the force fields and methods. We apply well-known and optimized simulation methods including AMBER and NAMD. The biomolecular simulation methods, when applied in a proper and consistent manner (utilizing the appropriate parameters and methods), allow us to better understand the structure, dynamics, interactions and energetics of proteins and nucleic acids
Keywords: Amber; Biomedical Research; CRISP; Computer Retrieval of Information on Scientific Projects Database; Funding; Goals; Grant; High Performance Computing; Institution; International Network for Strategic Initiatives in Global HIV Trials; Investigators; Methods; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nucleic Acids; Proteins; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Structure; United States National Institutes of Health; gene product; simulation
Project start date: 2009-08-01
Project end date: 2010-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
5P41RR006009-19_6308 (2009): $771
USING AMBER TO PROBE STRUCTURE, DYNAMICS AND INTERACTION
Thomas E Cheatham, Associate Professor
University Of California San Francisco, 3333 California St., Ste 315, San Francisco, Ca 94143-0962
Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the past decade, we have developed and applied the AMBER suite of programs for biomolecular simulation to a wide variety of biomolecular systems. In addition, our group has developed the ptraj software for trajectory analysis. A significant part of our work involves visualization of the macromolecular structures and we have been a long-time user of both Midas and the Chimera suite of software. Recent progress is highlighted in our publications
Keywords: Amber; Biomedical Computing; CRISP; Chimera; Chimera organism; Computer Programs; Computer Retrieval of Information on Scientific Projects Database; Computer software; Funding; Grant; Imagery; Informatics; Institution; Investigators; Macromolecular Structure; Molecular Structure; NIH; National Institutes of Health; National Institutes of Health (U.S.); Programs (PT); Programs [Publication Type]; Publications; Research; Research Personnel; Research Resources; Researchers; Resources; Scientific Publication; Software; Source; Structure; System; System, LOINC Axis 4; Time; United States National Institutes of Health; Visualization; Work; bio-computation; bio-computing; biocomputing; biomedical computation; computer program/software; programs; simulation
Project start date: 2009-07-01
Project end date: 2010-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
5P41RR001081-32_5729 (2009): $8911
Thomas E Cheatham
Mellon Pitts Corporation (mpc Corp) Pittsburgh, Pa 152133890
Grant 5P41RR006009-100142 from National Center For Research Resources
Abstract: No Available
Keywords: bioengineering /biomedical engineering, biological product, biomedical resource, computer
MOLECULAR DYNAMICS SIMULATIONS OF PROTEINS And NUCLEIC ACIDS
Thomas E Cheatham, Assistant Professor
University Of California San Francisco 3333 California St., Ste 315 San Francisco, Ca 941430962
Grant 3P41RR001081-22S10023 from National Center For Research Resources
Abstract: Molecular dynamics and free energy simulation methodologies have been employed to investigate the structure, flexibility and dynamics of a variety of protein and nucleic acid systems in solution. Solvated molecular dynamics simulations give realistic information into sequence specific nucleic acid structure, hydration and dynamics which give insight into function. Continuum methods have been applied as an analysis tool to give insight into the relative energetics of a variety of systems. The focus of our work is the development of accurate force field parameters and dependence of the environment on nucleic acid structure. We are using MidasPlus extensively as our visualization tool.
Keywords: biological product, biomedical resource, protein
Project start date: 1999-07-01
Project end date: 2000-06-30
Insight Into Biomolecular Structure, Dynamics, Interactions And Energetic From
Thomas E Cheatham
Mellon Pitts Corporation (mpc Corp) Pittsburgh, Pa 152133890
Grant 5P41RR006009-150309 from National Center For Research Resources IRG: ZRG1
Keywords: bioenergetics, biomedical resource, intermolecular interaction, molecular dynamics
Project start date: 2004-08-01
Project end date: 2005-07-31
Thomas E Cheatham
Mellon Pitts Corporation (mpc Corp) Pittsburgh, Pa 152133890
Grant 5P41RR006009-130142 from National Center For Research Resources
Keywords: bioengineering /biomedical engineering, biological product, biomedical resource, computer
Sponsored Links Excellgen http://Excellgen.com
MOLECULAR DYNAMICS SIMULATIONS OF PROTEINS And NUCLEIC ACIDS
Thomas E Cheatham, Assistant Professor
University Of California San Francisco 3333 California St., Ste 315 San Francisco, Ca 941430962
Grant 2P41RR001081-200023 from National Center For Research Resources
Keywords: biological product, biomedical resource, computer, nucleic acid, protein
Project start date: 1997-07-15
Project end date: 1998-06-30
Thomas E Cheatham
Mellon Pitts Corporation (mpc Corp) Pittsburgh, Pa 152133890
Grant 5P41RR006009-070191 from National Center For Research Resources