Fast design of arbitrary length loops in proteins using InteractiveRosetta

William F Hooper,Christopher Bystroff,Xing Wang,Benjamin D Walcott

doi:10.1186/s12859-018-2345-5

William F Hooper, Christopher Bystroff + Show 2 more

Open Access

https://doi.org/10.1186/s12859-018-2345-5

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Abstract

BackgroundWith increasing interest in ab initio protein design, there is a desire to be able to fully explore the design space of insertions and deletions. Nature inserts and deletes residues to optimize energy and function, but allowing variable length indels in the context of an interactive protein design session presents challenges with regard to speed and accuracy.ResultsHere we present a new module (INDEL) for InteractiveRosetta which allows the user to specify a range of lengths for a desired indel, and which returns a set of low energy backbones in a matter of seconds. To make the loop search fast, loop anchor points are geometrically hashed using C α-C α and C β-C β distances, and the hash is mapped to start and end points in a pre-compiled random access file of non-redundant, protein backbone coordinates. Loops with superposable anchors are filtered for collisions and returned to InteractiveRosetta as poly-alanine for display and selective incorporation into the design template. Sidechains can then be added using RosettaDesign tools.ConclusionsINDEL was able to find viable loops in 100% of 500 attempts for all lengths from 3 to 20 residues. INDEL has been applied to the task of designing a domain-swapping loop for T7-endonuclease I, changing its specificity from Holliday junctions to paranemic crossover (PX) DNA.

Highlights

With increasing interest in ab initio protein design, there is a desire to be able to fully explore the design space of insertions and deletions
We show that INDEL can be applied to a system that contains multiple chains, protein and Paranemic crossover deoxyribonucleic acids (DNA) together, and a system which contains homo-dimeric symmetry, where two copies of the loop are designed simultaneously
In benchmarking the code using a variety of loop length, we found the loops were returned in under 13 s in the vast majority of cases, and never did it take over 70 s to return an answer, regardless of length or location (Fig. 1)

Summary

Introduction

With increasing interest in ab initio protein design, there is a desire to be able to fully explore the design space of insertions and deletions. Nature inserts and deletes residues to optimize energy and function, but allowing variable length indels in the context of an interactive protein design session presents challenges with regard to speed and accuracy. Computational protein design is the task of finding an energy-optimal amino acid sequence for a backbone structure. Simplifying assumptions, such as fixed backbone atoms and discrete side chain conformations [1, 2], have been necessary because of the prohibitive size of the computational sequence search space.

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