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Published by: Humair Shaheen on Dec 16, 2011
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Coarsification of Large Biomolecular Systems

Kishor Bhalerao*, Kurt Anderson† Computational Dynamics Lab Department of Mechanical, Aerospace and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy-12180, NY, USA Email:*bhalek@rpi.edu, † anderk5@rpi.edu EXTENDED ABSTRACT Molecular Dynamics (MD) offers the ability to capture, investigate, analyze and understand the underlying mechanism by which important processes occur. Unfortunately MD simulation using standard atomistic models quickly run into significant challenges for all but the most elementary systems1 2 3. This is because classical molecular dynamics propagates the motion of molecular models by solving the equations of motion for all the atoms in the model. In the fully atomistic case, (i.e. Newton’s equations of motion are derived and solved for every atom of the system), we have the most direct application of the physics involved, with the associated implementation being in many regards conceptually the simplest and easiest to apply. Unfortunately, due to the nature of the molecular interactions, specifically the stiffness of the bonds and other interactions, integrating these equations requires very fine time steps in order to maintain temporal integrator stability (the highest frequency of the systems must be accurately captured). Depending on the temporal integration method used, at least one system wide force determination (to drive the equations of motion) must be performed and this determination is extremely expensive (often the most costly aspect) for large systems. Thus, though conceptually simple and easy to implement, such brute force methods grind to an effective halt under the burden of their sub-femtosecond (< 1015 sec.) required time steps and associated expensive force determinations. The computational cost of advancing the simulation at sub-femto second time steps, in an effort capture phenomena in the microseconds+ domain is prohibitive. As such the state of the art simulations of many important biomolecular systems tend to be limited to the nano-second domain. Many efforts have focused on overcoming the strict time step limits in MD simulations. If larger stable integration time steps can be taken, then fewer expensive force determinations (which generally dominate the overall cost) are needed. These forces can be categorized into highly stiff localized interactions, which include the axial, torsional and dihedral interactions, and global conformational interactions such as the long range Coulombic and Lennard Jones interactions4. The stiff localized interactions control the high frequency vibrational motion of these particles while the lower frequency global interactions dominate the conformational motion of the system. Consequently, modeling methods for improving computational efficiency of these complex molecular systems is an active area of research. In these efforts, one of the objectives is to develop coarse grained representations of the systems by imposing kinematic constraints that eliminate the high frequency content of the system without adversely compromising the fidelity of the model with regard to representing key behavior. To date, the model coarsening process has been guided primarily by experience and observed results without any well defined metrics. Such knowledge based approaches are valuable but tend to be very limited in how they can be applied when a sufficient knowledge base is not available. It is preferred that a rigorous yet general physics or math based approach be developed for guiding the model coarsening process. In this manner, a robust methods might be developed which may be successfully applied to complex molecular system models for which no prior knowledge base is needed.

Pande. and M. Rhee. No 9. particularly in regard to model coarsegraining which is not static. D. Mandzuik. A. 867-892. Sorin. Y. Prentice Hall. E. and V. Barth. the coarsification of Alanine Dipeptide molecule is analyzed. Vol 18. International Journal of Robotics Research.In this paper we discuss the advantages of using Featherstones’s Divide and Conquer Framework5 for developing coarse grain models. IEEE Computing in Science and Engineering ( Special issue on Computational Chemistry). As a test case. S. J. How well can simulations predict protein folding kinetics and thermodynamics. Schlick. Biomolecular dynamics at long time timesteps: Bridging the timescale gap between simulation and experimentation. 26:181–222. T. 1 T. Annual review of Biophysics and Biomolecular Structure. Part 1&2. 2001 4 5 R. which could be used to quantify the latent degrees of freedom. 34:43–69. We explore the possibility of using sensitivity analysis as a tool to identify latent degrees of freedom and propose an alternative metric. Schlick. Annual Review of Biophysics and Biomolecular Structure. 1997. 2000. Leach. Snow. 2005. but adapts as the conformation of the system changes during the simuloation. 1999. E. 3 2 C. pp. Computational challenges in simulating large DNA over long times. A Divide-and-Conquer Articulated-Body Algorithm for Parallel O(log(n)) Calculation of Rigid-Body Dynamics. Molecular Modelling: Principles and Applications. . Featherstone. 2:38–51. M.R.

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