It was a nice surprise to notice the following 3DNA citation in a Nature article, titled Selective small-molecule inhibition of an RNA structural element (doi:10.1038/nature15542). Moreover, the work came from Merck Research Laboratories, reporting a novel selective chemical modulator (ribocil) to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth.
Homology modelling. A homology model of the E. coli FMN aptamer was constructed using program mutate_bases53 of the 3DNA package using the F. nucleatum impX riboswitch aptamer X-ray structure as the template and the FMN aptamer alignment of E. coli, F. nucleatum, P. aeruginosa and A. baumannii (Extended Data Fig. 5). All nucleotide insertions in the E. coli sequence were removed in the model (Extended Data Fig. 5). There are 34 base changes among the 111 nucleotides modelled. Base pairing when present remains consistent. Energy minimization at A92 was performed to avoid VDW clashes using Macromodel (Schrodinger, LLC).
In retrospect, the mutate_bases program was created in response to repeated requests from 3DNA users, initially mostly for modeling DNA-protein complexes. The program was first coded as a Perl script, and later on rewritten in ANSI C for efficiency. Since v2.1,
mutate_bases has become an essential component of 3DNA, on a par with
fiber etc. As I noted in the post documenting the program
mutate_baseshas been designed to solve the in silico base mutation problem in a practical sense: robust and efficient, getting its job done and then out of the way. The program can have many possible applications: in addition to perform base-pair mutations in DNA-protein complexes, it should also prove handy in RNA modeling and in providing initial structures for QM/MM/MD energy calculations, and in DNA/RNA modeling studies.
The Merck Nature paper is the first time ever that the 3DNA
mutate_bases program has been put in the spotlight. Hopefully more such applications/citations will appear in the future as the community begin to appreciate the value of this little gem.