Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling

DJ Mandell, EA Coutsias, T Kortemme - Nature methods, 2009 - nature.com
Nature methods, 2009nature.com
To the Editor: Proteins exploit the conformational variability of loop regions to carry out
diverse biological tasks including molecular recognition and signal transduction. New
algorithms to engineer these functions by combining loop building and sequence design
therefore have enormous practical applications but require highresolution 'loop
reconstruction': the modeling of protein loop conformations, given the amino acid sequence.
Loop reconstruction in protein design may be simplified conceptually by restricting changes …
To the Editor: Proteins exploit the conformational variability of loop regions to carry out diverse biological tasks including molecular recognition and signal transduction. New algorithms to engineer these functions by combining loop building and sequence design therefore have enormous practical applications but require highresolution ‘loop reconstruction’: the modeling of protein loop conformations, given the amino acid sequence. Loop reconstruction in protein design may be simplified conceptually by restricting changes to the functional loop regions. However, despite progress in loop prediction methods1, 2, design applications are limited by the difficulty in modeling purely local conformational moves and by the need for advances in sampling and evaluating loop conformations. Here we address these challenges with a robotics-inspired local loop reconstruction method for peptide chains, called kinematic closure (KIC). Calculating the accessible conformations of objects subject to constraints, such as determining the possible positions of the interior joints of a robot arm given fixed positions for the shoulder and fingertips, has been well-studied in inverse kinematics, a subfield of robotics. Building on the first3 and subsequent applications (Supplementary Methods) of kinematics to protein modeling, the KIC method presented here analytically determines all mechanically accessible conformations for 6 torsions of a peptide chain of any length, while simultaneously sampling the remaining torsions and N-Cα-C bond angles using polynomial resultants4
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