Recent advances in the field of structural biology and quantitative proteomics mean that there is now sufficient information available to allow the construction of meaningful, working molecular models of physiological environments. Such environmental models, when coupled to simulation methods that enable the dynamics of the systems to be modeled, will allow key biochemical processes such as protein folding and protein-protein association events to be observed in settings that much more closely mimic those encountered in real life. The project proposed here has two major objectives which will be pursued in parallel: (1) molecular simulation methods that have been under development in the PI's laboratory for some years will be extended and accelerated to make them suitable for use in simulating the dynamics of very large-scale macromolecular systems (e.g. comprising 10,000 macromolecules), (2) structural biological and quantitative proteomics data will be utilized to build preliminary 3D models of four different environments in the model prokaryote Escherichia coli: the cytoplasm, periplasm, and inner and outer-membranes

Public Health Relevance

Understanding the molecular processes that define life, and the way that these processes can be altered in disease states and under the influence of drugs, may ultimately require a true molecular level picture of intracellular events to be obtained. The proposed research aims to combine recent advances in the fields of structural biology and quantitative proteomics to build working, molecular models of physiological environments, such as those found inside the bacterium Escherichia coli. Observing key processes such as protein folding and associations occurring in situ may have the potential, eventually, of leading to new avenues for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM087290-01
Application #
7631105
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
2009-09-21
Project End
2011-08-31
Budget Start
2009-09-21
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$260,000
Indirect Cost
Name
University of Iowa
Department
Biochemistry
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Lay, Wesley K; Miller, Mark S; Elcock, Adrian H (2017) Reparameterization of Solute-Solute Interactions for Amino Acid-Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations. J Chem Theory Comput 13:1874-1882
Miller, Mark S; Lay, Wesley K; Li, Shuxiang et al. (2017) Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations. J Chem Theory Comput 13:1812-1826
Hacker, William C; Li, Shuxiang; Elcock, Adrian H (2017) Features of genomic organization in a nucleotide-resolution molecular model of the Escherichia coli chromosome. Nucleic Acids Res 45:7541-7554
Andrews, Casey T; Campbell, Brady A; Elcock, Adrian H (2017) Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations. J Chem Theory Comput 13:1794-1811
Lay, Wesley K; Miller, Mark S; Elcock, Adrian H (2017) Correction to Reparameterization of Solute-Solute Interactions for Amino Acid-Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations. J Chem Theory Comput 13:3076
Chen, Ran; Subramanyam, Shyamal; Elcock, Adrian H et al. (2016) Dynamic binding of replication protein a is required for DNA repair. Nucleic Acids Res 44:5758-72
Miller, Mark S; Lay, Wesley K; Elcock, Adrian H (2016) Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization. J Phys Chem B 120:8217-29
Lay, Wesley K; Miller, Mark S; Elcock, Adrian H (2016) Optimizing Solute-Solute Interactions in the GLYCAM06 and CHARMM36 Carbohydrate Force Fields Using Osmotic Pressure Measurements. J Chem Theory Comput 12:1401-7
Frembgen-Kesner, Tamara; Andrews, Casey T; Li, Shuxiang et al. (2015) Parametrization of Backbone Flexibility in a Coarse-Grained Force Field for Proteins (COFFDROP) Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of All Possible Two-Residue Peptides. J Chem Theory Comput 11:2341-54
Schrodt, Michael V; Andrews, Casey T; Elcock, Adrian H (2015) Large-Scale Analysis of 48 DNA and 48 RNA Tetranucleotides Studied by 1 ?s Explicit-Solvent Molecular Dynamics Simulations. J Chem Theory Comput 11:5906-17

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