Substitution of multiple AAs led to an abrogation of binding in the remaining peptides.
Then there are changes that hit Sundays harder, like the substitution of multiple three-day weekends for the old two- or three-week vacation, so people are not around on Sundays to buy the paper.
Although various oligonucleotide backbone modifications have been invented for more efficient binding to complementary RNA [23, 24], these modifications require substitution of multiple nucleotides.
The evolution of high levels of resistance to an antibiotic via mutation sometimes involves the substitution of multiple mutations.
Epistasis, the non-additive interaction of mutations at multiple loci, plays a major role when resistance to antibiotics requires the sequential substitution of multiple mutations.
In the model, substitution of multiple phenylalanine residues by serine [ 11] led to a predicted increase of the ratio of turn-forming residues in the formula and thus to a lowered predicted solubility in E. coli.
However, there is growing evidence that high levels of antibiotic resistance evolve by the substitution of multiple mutations that confer resistance to the same antibiotic (Weinreich et al. 2006; Bruchmann et al. 2013; Farhat et al. 2013; Zhang et al. 2013).
The number of polymorphic sites is lower than the sum of synonymous and non-synonymous substitutions because of multiple different bases in some polymorphic sites.
In some cases, they can even produce complex mutations (e.g. tandem base pair substitutions and clusters of multiple, closely spaced mutations) as was shown recently for Pol ζ (Stone, Lujan, Kunkel 2012).
Another challenge associated with rate estimation is the underestimation of the number of substitutions along some branches, as a result of multiple substitutions at some sites, particularly as phylogenetic distance (i.e. branch length) increases [29], [30].
