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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Aristoff, David; Bello-Rivas, Juan M; Elber, Ron (2016) A MATHEMATICAL FRAMEWORK FOR EXACT MILESTONING. Multiscale Model Simul 14:301-322
Cardenas, Alfredo E; Elber, Ron (2016) Markovian and Non-Markovian Modeling of Membrane Dynamics with Milestoning. J Phys Chem B 120:8208-16
Chen, Szu-Hua; Meller, Jaroslaw; Elber, Ron (2016) Comprehensive analysis of sequences of a protein switch. Protein Sci 25:135-46
Bello-Rivas, Juan M; Elber, Ron (2016) Simulations of thermodynamics and kinetics on rough energy landscapes with milestoning. J Comput Chem 37:602-13
Elber, Ron (2016) Perspective: Computer simulations of long time dynamics. J Chem Phys 144:060901
Bello-Rivas, Juan M; Elber, Ron (2015) Exact milestoning. J Chem Phys 142:094102
Mugnai, Mauro L; Shi, Yue; Keatinge-Clay, Adrian T et al. (2015) Molecular dynamics studies of modular polyketide synthase ketoreductase stereospecificity. Biochemistry 54:2346-59
Shrestha, Rebika; Cardenas, Alfredo E; Elber, Ron et al. (2015) Measurement of the membrane dipole electric field in DMPC vesicles using vibrational shifts of p-cyanophenylalanine and molecular dynamics simulations. J Phys Chem B 119:2869-76
Cardenas, Alfredo E; Shrestha, Rebika; Webb, Lauren J et al. (2015) Membrane permeation of a peptide: it is better to be positive. J Phys Chem B 119:6412-20
Di Pierro, Michele; Elber, Ron; Leimkuhler, Benedict (2015) A Stochastic Algorithm for the Isobaric-Isothermal Ensemble with Ewald Summations for All Long Range Forces. J Chem Theory Comput 11:5624-37

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