Atomically detailed simulations of a biomolecular process can provide significant insight to mechanisms and function, and are therefore widely used. Nevertheless, enthusiasm for these simulations is somewhat reduced when we consider their time scale limitation. Time scales of Molecular Dynamics (MD) simulations are restricted to a few microseconds, significantly shorter than time scales of many processes in molecular biophysics, such as rapid and slow folding, conformational transitions and activation, and signal transduction. In the previous funding periods we focused on the calculation of approximate trajectories that describe long time (even millisecond) processes. The trajectories compared favorably with experiments on structural properties of paths. However, the calculation of kinetic properties proved difficult. Determining rate is important since kinetic of cellular processes describes function;it is also at the core of the timely field of System Biology. We developed a new computational technique, Milestoning, to calculate rates. In the next grant period we plan to advance the new methodology, and to compute the kinetics of myosin recovery stroke and allosteric transition in Scapharca hemoglobin. Our algorithms are implemented in the Molecular Dynamics package MOIL which continues to be freely available at

Public Health Relevance

The algorithm developed in the grant will help predict kinetics (and function) of proteins and are likely to give better understanding of proteins and their interactions with other molecules (like drugs).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Preusch, Peter C
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University of Texas Austin
Engineering (All Types)
Schools of Engineering
United States
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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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