Conformational transitions of proteins are essential for signaling, activation, generation of mechanical energy, regulation and more. They are controlled by subtle changes in the environment and by binding of small molecules and are therefore best modelled at the atomic resolution. However, simulations using atomically detailed descriptions are expensive. Straightforward simulations are restricted to time scale (microseconds) significantly shorter than many important conformational transition of proteins, protein- protein and protein-nucleotide complexes. Our program focused on the development of theory and algorithms for the study of conformational transitions of biological molecules at the correct time scale and at atomic details. To that end we have developed efficient algorithms to compute reaction paths and have applied them to numerous biophysics problems. In the last few years we have extended our set of tools to include Milestoning, a spatial and temporal coarse graining approach to compute thermodynamic and kinetic parameters associated with a reaction path (or with a reaction space). In the present cycle we propose further advancement to the combined method of reaction path calculations and Milestoning which will include expansion of the reaction space under consideration, evaluation of memory effect, and further software enhancements. We will also extend and deepen our investigations of systems we have looked at in the past (myosin II and hemoglobin) and will investigate new systems in tight collaboration with experiments; (i) HIV RT (in collaboration with Ken Johnson) and (ii) IHF (in collaboration with Anjum Ansari). This tight collaboration is expected to shed new light on mechanisms of enzyme specificity and on regulation of transcription.

Public Health Relevance

Conformational transitions of proteins are essential for signaling, activation, generation of mechanical energy, regulation and more. Our study focuses on protein flexibility in four examples and will impact research on protein function, drug design, and drug resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059796-16
Application #
8813583
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter
Project Start
2000-03-01
Project End
2017-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
16
Fiscal Year
2015
Total Cost
$282,540
Indirect Cost
$90,735
Name
University of Texas Austin
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Fathizadeh, Arman; Elber, Ron (2018) Ion Permeation Through a Phospholipid Membrane: Transition State, Path Splitting, and Calculation of Permeability. J Chem Theory Comput :
Templeton, Clark; Elber, Ron (2018) Why Does RNA Collapse? The Importance of Water in a Simulation Study of Helix-Junction-Helix Systems. J Am Chem Soc :
Ma, Piao; Cardenas, Alfredo E; Chaudhari, Mangesh I et al. (2018) Probing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning. J Phys Chem B 122:10296-10305
Ma, Piao; Cardenas, Alfredo E; Chaudhari, Mangesh I et al. (2017) The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory. J Am Chem Soc 139:14837-14840
Elber, Ron; Bello-Rivas, Juan M; Ma, Piao et al. (2017) Calculating Iso-Committor Surfaces as Optimal Reaction Coordinates with Milestoning. Entropy (Basel) 19:
Atis, Murat; Johnson, Kenneth A; Elber, Ron (2017) Pyrophosphate Release in the Protein HIV Reverse Transcriptase. J Phys Chem B 121:9557-9565
Shrestha, Rebika; Anderson, Cari M; Cardenas, Alfredo E et al. (2017) Direct Measurement of the Effect of Cholesterol and 6-Ketocholestanol on the Membrane Dipole Electric Field Using Vibrational Stark Effect Spectroscopy Coupled with Molecular Dynamics Simulations. J Phys Chem B 121:3424-3436
Templeton, Clark; Chen, Szu-Hua; Fathizadeh, Arman et al. (2017) Rock climbing: A local-global algorithm to compute minimum energy and minimum free energy pathways. J Chem Phys 147:152718
Aristoff, David; Bello-Rivas, Juan M; Elber, Ron (2016) A MATHEMATICAL FRAMEWORK FOR EXACT MILESTONING. Multiscale Model Simul 14:301-322
Chen, Szu-Hua; Meller, Jaroslaw; Elber, Ron (2016) Comprehensive analysis of sequences of a protein switch. Protein Sci 25:135-46

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