The results of Gong et al. suggest that increasing the stability of a protein (y axis) above a certain threshold has no effect on fitness, which means that protein evolution can occur along multiple alternative routes. However, fitness decreases rapidly when stability drops below the threshold (red region), in which case evolution will select for mutations that increase stability. Four sites within a protein are shown, with two possible states for each site, indicated by the presence/absence of the asterisk. Single point mutations are indicated by solid arrows, double mutations are indicated by dashed arrows. Consider the case where a* and c* are mutations that help a protein to evade the immune system and, like the great majority of random mutations, they reduce the stability of the protein relative to the parent protein (abcd). However, mutations that increase stability, such as b* and d*, can compensate for mutations that reduce stability, which means that several proteins containing a* and/or c* can remain above the stability threshold required for optimal fitness.