The goal of the proposed research is to bring computer simulation of protein molecular dynamics to the point where it is sufficiently reliable and realistic to allow prediction of energetic, structural and dynamic properties of these complicated systems. This will he accomplished by asking specific questions and answering them by simulation and detailed analysis of specific applications as follows: 1. Are simulations of proteins in solution sufficiently stable to allow the extended simulation needed to sample rare events and accumulate accurate averages? Extending simulations of bovine pancreatic trypsin inhibitor (BPTl) in solution well beyond 100 picoseconds (ps) will confirm our methodological advances (use of all-atom energy functions, a flexible water molecule and a smoothly truncated nonbonded potential together with strict insistence on energy conservation). 2. How does the solution structure of a protein differ from the crystal structure? Analysis of the extended BPTI trajectory by calculating the spectiral densities of each inter-proton vector, will make it possible to derive a more accurate solution structure from nuclear magnetic resonance experiments. Comparisons to inelastic neutron scattering data will also be made. 3. Can simple energy functions and classical dynamics reproduce the details of protein x-ray structures? We will simulate the dynamics of two well-refined, high-resolution protein structures, BPTI and crambin in their native crystal lattices. Systematic differences between the calculated time- averaged structure and the x-ray structure will be used to modify the energy parameters. 4. How does water penetrate into and disrupt native protein structure in the first stages of unfolding? Which interactions are weakened first, the polar hydrogen bonds or the non-polar van der Waals' interactions? How rapidly do such """"""""unfolding"""""""" fluctuations occur under normal and denaturing conditions? We will investigate the stability of native BPTI in solution as temperature, density (equivalent to pressure) and patterns of disulphide bonding are changed. These methods will also used on simpler systems such as a-helices and B-hairpins in solutions. 5. By what path and at what rate are water molecules expelled from protein binding sites? We will apply these method to larger proteins, ribonuclease and the trypsin/BPTl complex, which are also being studied experimentally.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM041455-02
Application #
3299664
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Sim, Adelene Y L; Minary, Peter; Levitt, Michael (2012) Modeling nucleic acids. Curr Opin Struct Biol 22:273-8
Moreno-Hernández, Sergio; Levitt, Michael (2012) Comparative modeling and protein-like features of hydrophobic-polar models on a two-dimensional lattice. Proteins 80:1683-93
Sim, Adelene Y L; Levitt, Michael; Minary, Peter (2012) Modeling and design by hierarchical natural moves. Proc Natl Acad Sci U S A 109:2890-5
Sim, Adelene Y L; Levitt, Michael (2011) Clustering to identify RNA conformations constrained by secondary structure. Proc Natl Acad Sci U S A 108:3590-5
Bernauer, Julie; Huang, Xuhui; Sim, Adelene Y L et al. (2011) Fully differentiable coarse-grained and all-atom knowledge-based potentials for RNA structure evaluation. RNA 17:1066-75
Samson, Abraham O; Levitt, Michael (2011) Normal modes of prion proteins: from native to infectious particle. Biochemistry 50:2243-8
Bray, Jenelle K; Weiss, Dahlia R; Levitt, Michael (2011) Optimized torsion-angle normal modes reproduce conformational changes more accurately than cartesian modes. Biophys J 101:2966-9
Chopra, Gaurav; Levitt, Michael (2011) Remarkable patterns of surface water ordering around polarized buckminsterfullerene. Proc Natl Acad Sci U S A 108:14455-60
Huang, Xuhui; Wang, Dong; Weiss, Dahlia R et al. (2010) RNA polymerase II trigger loop residues stabilize and position the incoming nucleotide triphosphate in transcription. Proc Natl Acad Sci U S A 107:15745-50
Minary, Peter; Levitt, Michael (2010) Conformational optimization with natural degrees of freedom: a novel stochastic chain closure algorithm. J Comput Biol 17:993-1010

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