Constrained geometric simulation of diffusive motion in proteins

Abstract

We describe a new computational method, FRODA (framework rigidity optimized dynamic algorithm), for exploring the internal mobility of proteins. The rigid regions in the protein are first determined, and then replaced by ghost templates which are used to guide the movements of the atoms in the protein. Using random moves, the available conformational phase space of a 100 residue protein can be well explored in approximately 10-100 min of computer time using a single processor. All of the covalent, hydrophobic and hydrogen bond constraints are maintained, and van der Waals overlaps are avoided, throughout the simulation. We illustrate the results of a FRODA simulation on barnase, and show that good agreement is obtained with nuclear magnetic resonance experiments. We additionally show how FRODA can be used to find a pathway from one conformation to another. This directed dynamics is illustrated with the protein dihydrofolate reductase. M This article features online multimedia enhancements

Dynamic personalities of proteins

“…Unfortunately, protein dynamics on the microsecond-to-millisecond timescale is currently out of reach for conventional molecular-dynamics simulations. To overcome this restriction, a large variety of approaches that simplify force fields have been developed, including normal mode analysis 50,51 , gaussian network models 52 , FIRST (floppy inclusion and rigid substructure topography) 53 , FRODA (framework rigidity optimized dynamic algorithm) 54 and Gō models 49 . Alternatively, the dynamic process is accelerated by external force to access this timescale (used in methods such as targeted, steered and accelerated molecular-dynamics simulations 47,[55][56][57] ), or prior knowledge about features of the reaction coordinate (umbrella sampling algorithms to construct a potential of mean force 58 ) or the transition end points (transition-path sampling 59 ) is necessary.…”

GASP: software for geometric simulations of flexibility in polyhedral and molecular framework structures

“…[28] The 'FRODA' approach (framework rigidity optimised dynamic algorithm) makes use of templates to represent the geometry of portions of a protein structure. Rigid groups are identified using the 'FIRST' rigidity analysis software, [29] within which FRODA is implemented, and vary in size from single methyl groups to clusters spanning multiple secondary structure units or entire protein domains, depending on the distribution of covalent and non-covalent constraints in the protein.…”

An Interfacial Thermodynamics Model for Protein Stability

“…Instead, excluded volume effects due to van der Waals interactions are included in geometrical simulation that allows rigid clusters to wiggle about without violating any distance constraint, or without atoms passing through one another. FRODA (Framework Rigidity Optimized Dynamics Algorithm) is one method [Wells, et al 2005;Farrell, et al 2010], among others [Lei, et al 2004;Thomas, et al 2007;Jimenez-Roldan, et al 2011;Yao, et al 2012] that uses FIRST to identify a native RCD that is preserved during the simulation. FRODA efficiently explores the native state ensemble of conformations [Jacobs, 2010;David & Jacobs 2011].…”