Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface

PLoS Computational Biology
Anna U LowegardBruce R Donald

Abstract

The K* algorithm provably approximates partition functions for a set of states (e.g., protein, ligand, and protein-ligand complex) to a user-specified accuracy ε. Often, reaching an ε-approximation for a particular set of partition functions takes a prohibitive amount of time and space. To alleviate some of this cost, we introduce two new algorithms into the osprey suite for protein design: fries, a Fast Removal of Inadequately Energied Sequences, and EWAK*, an Energy Window Approximation to K*. fries pre-processes the sequence space to limit a design to only the most stable, energetically favorable sequence possibilities. EWAK* then takes this pruned sequence space as input and, using a user-specified energy window, calculates K* scores using the lowest energy conformations. We expect fries/EWAK* to be most useful in cases where there are many unstable sequences in the design sequence space and when users are satisfied with enumerating the low-energy ensemble of conformations. In combination, these algorithms provably retain calculational accuracy while limiting the input sequence space and the conformations included in each partition function calculation to only the most energetically favorable, effectively reducing runtime w...Continue Reading

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Citations

Apr 23, 2021·Protein Engineering, Design & Selection : PEDS·Ben A Meinen, Christopher D Bahl
Aug 31, 2021·Current Opinion in Structural Biology·Eleni Michael, Thomas Simonson

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Methods Mentioned

BETA
bio-layer interferometry
NMR
biosensors

Software Mentioned

EWAK
Octet Data Analysis HT
osprey
FortéBio Data Analysis HT
BBK
fries
osprey ( Open Source Protein Redesign for You )
FortéBio
CSPD

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