The selected mutations were introduced in equilibrated wild type receptor systems from GPCRmd, which were subsequently re-equilibrated to run production 500 ns MD simulations following the GPCRmd pipeline. One of the selected mutations did not run successfully therefore it was discarded from the analysis (AA2AR H278N 7.42) . Most mutant trajectories showed deviations from wild type trajectories in terms of RMSF (Figure ), with the exception of AA1R and CCR5 mutants. The deviations were sometimes in the vicinity of the mutation (i.e. AA2AR M177A 5.40 , N181A 5.43 , Y271A 7.35 ; ARDB2 D130N 3.49 , S203A 5.43 , V317A 7.43 ; ACM2 D103E 3.32 , V421L 7.33 ), but most commonly spawned across the whole sequence or altered stability in distant regions. For example, in AA2AR L85A 3.33 increased flexibility in ICL2 and ECL2 and S91A 3.39 in ICL3 and TM6. Moreover, adjacent mutations that triggered different effects were observed. For example, in ADRB2, S203A 5.43 decreased stability in TM1, ICL2, and ECL3, while S204A 5.44 decreased stability in TM2 and TM4, while increasing stability in ICL3. Of note, in ACM2 D103E 3.32 and D103N 3.32 triggered similar higher flexibility in ECL1 and ECL2, with an overall differential pattern of lower stability in D103E 3.32 . In general, the mutations with smaller dynamic fluctuations from wild type also corresponded to those with a smaller effect in bioactivity, such as AA1R R291C 7.56 and R296C 8.51 , and ADRB2 V317A 7.43 (Figures ).