Supplementary 3 Amino Acid Conservation Scores The layers for assigning grades are as follows. from -1.299 to -1.010 the grade is 9 from -1.010 to -0.722 the grade is 8 from -0.722 to -0.433 the grade is 7 from -0.433 to -0.144 the grade is 6 from -0.144 to 0.288 the grade is 5 from 0.288 to 0.865 the grade is 4 from 0.865 to 1.442 the grade is 3 from 1.442 to 2.019 the grade is 2 from 2.019 to 2.596 the grade is 1 If the difference between the colors of the Confidence interval colors is more than 3 or the msa number (Under the column titled MSA) is less than 6, there is insufficient data and an * appears in the COLOR column. - POS: The position of the AA in the SEQRES derived sequence. - SEQ: The SEQRES derived sequence in one letter code. - 3LATOM: The ATOM derived sequence in three letter code, including the AA's positions as they appear in the PDB file and the chain identifier. - Score: The normalized conservation scores. - Color: The color scale representing the conservation scores (9 - conserved, 1 - variable). - Confidence interval: When using the bayesian method for calculating rates, a confidence interval is assigned to each of the inferred evolutionary conservation scores. - Confidence interval colors: When using the bayesian method for calculating rates. The color scale representing the lower and upper bounds of the confidence interval. - MSA DATA: The number of aligned sequences having an amino acid (non-gapped) from the overall number of sequences at each position. - Residue variety: The residues variety at each position of the multiple sequence alignment.

 

Supplementary 3. Consurf grade scores for each amino acid of PAH protein POS SEQ 3LATOM Score (Normalized) Color Confidence interval Confidence interval colors B/E Function MSA DATA Residue variety 1 M MET:1:A -0.46 7* -1.100, -0.093 9,5 e NA 2/150 M 2 S SER:2:A -0.822 8* -1.211, -0.635 9,7 e f 4/150 S 3 T THR:3:A 0.278 5* -0.575,  0.994 7,3 e NA 3/150 T,A 4 A ALA:4:A 0.271 5* -0.635,  0.994 7,3 e NA 3/150 A,V 5 V VAL:5:A -0.502 7* -1.100, -0.193 9,6 e NA 3/150 V 6 L LEU:6:A -0.471 7* -1.100, -0.093 9,5 e NA 3/150 L 7 E GLU:7:A -0.669 7* -1.175, -0.439 9,7 e NA 4/150 E 8 N ASN:8:A 0.846 4* -0.093,  1.453 5,2 e NA 4/150 N,S,E 9 P PRO:9:A 0.931 3* -0.093,  1.453 5,2 e NA 4/150 P,G,R 10 G GLY:10:A 0.026 5* -0.746,  0.473 8,4 e NA 5/150 G,S 11 L LEU:11:A 0.081 5* -0.692,  0.473 7,4 e NA 5/150 L,T 12 G GLY:12:A 0.554 4 -0.364,  0.994 6,3 e NA 6/150 G,S,E 13 R ARG:13:A 1.504 2 0.473,  2.658 4,1 e NA 11/150 R,Q,G,K,D,P,N,S,E 14 K LYS:14:A 0.394 4 -0.282,  0.696 6,4 e NA 10/150 K,R,H,G,D 15 L LEU:15:A 1.035 3 0.019,  1.453 5,2 e NA 8/150 L,F,E,P 16 S SER:16:A 0.873 3 0.019,  1.453 5,2 b NA 9/150 S,D,K,E,A,N 17 D ASP:17:A 0.808 4 0.019,  1.453 5,2 e NA 8/150 D,E,K,V 18 F PHE:18:A 1.405 3 0.473,  2.658 4,1 e NA 8/150 F,G,A,S,K,D 19 G GLY:19:A 2.073 1 0.994,  2.658 3,1 e NA 11/150 G,R,Q,Y,D,S,T 20 Q GLN:20:A 2.042 1 0.994,  2.658 3,1 e NA 17/150 Q,L,Y,R,T,H,N,S,P,E 21 E GLU:21:A 2.24 1 0.994,  2.658 3,1 e NA 21/150 E,G,R,S,K,Q,H 22 T THR:22:A 1.784 2 0.696,  2.658 4,1 b NA 32/150 T,S,G,H,N,Q,D,E,L 23 S SER:23:A 1.143 3 0.473,  1.453 4,2 e NA 40/150 S,M,N,T,F,K,E,Q,A,G,P,R 24 Y TYR:24:A 0.396 4 -0.093,  0.696 5,4 b NA 45/150 Y,G,E,S,L,I,F,K 25 I ILE:25:A 1.183 3 0.473,  1.453 4,2 b NA 45/150 I,L,V,H,M,R,A,K,S,T,G,E 26 E GLU:26:A 2.292 1 0.994,  2.658 3,1 e NA 51/150 E,K,H,A,R,D,V,M,G,C,F,L,P,S,N,Q 27 D ASP:27:A 0.315 4 -0.093,  0.473 5,4 b NA 53/150 D,E,N,Q,I,V,K,P,S,H 28 N ASN:28:A 2.558 1 1.453,  2.658 2,1 e NA 56/150 N,H,E,G,Y,P,D,T,S,A,V,R,F,I 29 C CYS:29:A 2.509 1 1.453,  2.658 2,1 e NA 57/150 C,S,T,I,D,K,R,F,E,N,V,P,Q,Y,L,H 30 N ASN:30:A 0.918 3 0.473,  1.453 4,2 e NA 59/150 N,S,T,D,E,A,P,C,G,L 31 Q GLN:31:A 2.269 1 0.994,  2.658 3,1 e NA 71/150 Q,E,K,M,S,D,G,C,N,P,R,A,V,T,L 32 N ASN:32:A 2.005 2 0.994,  2.658 3,1 e NA 81/150 N,S,D,G,E,A,T,P,I,R,K,Q,Y,L 33 G GLY:33:A 2.527 1 1.453,  2.658 2,1 b NA 87/150 G,S,N,E,K,R,T,A,I,Q,D,V,P,L 34 A ALA:34:A 1.468 2 0.696,  1.453 4,2 b NA 94/150 A,F,R,V,T,S,C,N,L,K,Q,H,M,I 35 I ILE:35:A 0.89 3 0.473,  0.994 4,3 b NA 104/150 I,V,M,S,T,A,L,F,N,R 36 S SER:36:A 0.031 5 -0.193,  0.147 6,5 b NA 113/150 S,T,E,C,H,Y,L,W,A,N,R,I,K,D 37 L LEU:37:A 0.973 3 0.473,  1.453 4,2 b NA 117/150 L,C,V,I,F 38 I ILE:38:A 0.977 3 0.473,  1.453 4,2 b NA 117/150 I,L,T,C,V,F,H,Y,S,M,A,Q,E 39 F PHE:39:A -0.408 6 -0.635, -0.282 7,6 b NA 117/150 F,Y,L,I,V,M 40 S SER:40:A -0.185 6 -0.439, -0.093 7,5 e NA 117/150 S,T,G,A,R,M,E,H,K,N 41 L LEU:41:A 0.267 5 -0.093,  0.473 5,4 b NA 117/150 L,V,P,M,S,I,F,A,T 42 K LYS:42:A 1.058 3 0.473,  1.453 4,2 e NA 120/150 K,P,R,Q,H,E,A,N,T,V,I,G,D,S,C 43 E GLU:43:A -0.444 7 -0.635, -0.364 7,6 e NA 120/150 E,D,Q,S,N,K,A,T,P,R 44 E GLU:44:A 0.894 3 0.473,  0.994 4,3 e NA 122/150 E,Q,K,S,R,N,T,D,A,H,G,C,V 45 V VAL:45:A 0.479 4 0.147,  0.696 5,4 e NA 122/150 V,A,S,I,P,T,N,L,G,F,K,M,C,Q 46 G GLY:46:A 0.089 5 -0.193,  0.295 6,4 e NA 122/150 G,S,D,T,P,N,A,E,L,K 47 A ALA:47:A 0.875 3 0.473,  0.994 4,3 e NA 122/150 A,I,S,C,T,D,E,G,V,H,N,P,R,M 48 L LEU:48:A -0.91 8 -1.062, -0.797 9,8 e f 123/150 L,F,V,I 49 A ALA:49:A 0.318 4 0.019,  0.473 5,4 e NA 123/150 A,V,S,G,I,E,D,K,P,F,Q,N,H,W,L,T,C,R 50 K LYS:50:A 0.894 3 0.473,  0.994 4,3 e NA 124/150 K,R,E,S,A,D,T,N,G,Q,L,F,H 51 V VAL:51:A 0.467 4 0.147,  0.696 5,4 b NA 124/150 V,A,M,S,T,I,Y,F,C,L 52 L LEU:52:A -0.683 7 -0.847, -0.575 8,7 e NA 124/150 L,F,V,M,N,G,T,A,I 53 R ARG:53:A 0.292 4 0.019,  0.473 5,4 e NA 124/150 R,K,N,H,S,Q,G,M,A,D,E 54 L LEU:54:A 1.61 2 0.994,  1.453 3,2 b NA 125/150 L,I,V,M,Y,T,C,A,R,F,H,E,P,K,S 55 F PHE:55:A -0.549 7 -0.746, -0.439 8,7 b NA 125/150 F,L,I,V,S 56 E GLU:56:A -0.056 5 -0.282,  0.147 6,5 e NA 126/150 E,Q,K,T,S,N,A,R,W,D,P 57 E GLU:57:A 0.75 4 0.295,  0.994 4,3 e NA 126/150 E,D,S,A,R,N,K,G,T,V,M,Y 58 N ASN:58:A 1.073 3 0.696,  1.453 4,2 e NA 124/150 N,K,R,H,Y,F,G,M,L,D,C,V,A,E 59 D ASP:59:A 1.197 3 0.696,  1.453 4,2 e NA 126/150 D,G,K,N,S,H,E,Q,A 60 V VAL:60:A 0.059 5 -0.193,  0.147 6,5 b NA 127/150 V,I,A,F,S,E,T,G,C 61 N ASN:61:A -0.296 6 -0.509, -0.193 7,6 e NA 128/150 N,S,T,D,Q,K,R,A,I,C,H 62 L LEU:62:A -0.33 6 -0.575, -0.193 7,6 e NA 128/150 L,I,M,V,T 63 T THR:63:A 1.146 3 0.696,  1.453 4,2 e NA 128/150 T,Y,H,M,L,A,K,V,F,I,R,S,Q,D,C,E 64 H HIS:64:A -0.782 8 -0.938, -0.692 8,7 e f 128/150 H,K,Y,L,R,S,D,E,Q

Supplementary 3 (Continued) 65 I ILE:65:A -0.76 8 -0.893, -0.692 8,7 e f 128/150 I,M,L,F,Y,V 66 E GLU:66:A -1.178 9 -1.281, -1.138 9,9 b s 128/150 E,H,Q,L,A 67 S SER:67:A -1.081 9 -1.175, -1.022 9,9 e f 128/150 S,T,V,N 68 R ARG:68:A -1.223 9 -1.318, -1.175 9,9 e f 128/150 R,H,K 69 P PRO:69:A 0.223 5 -0.093,  0.473 5,4 e NA 127/150 P,S,L,A,K,R,Q,T,D 70 S SER:70:A 0.142 5 -0.093,  0.295 5,4 e NA 127/150 S,A,G,M,V,C,P,K,N,R,T,D 71 R ARG:71:A 1.145 3 0.696,  1.453 4,2 e NA 128/150 R,Q,K,T,S,V,H,E,A,L,N,P 72 L LEU:72:A 1.43 3 0.994,  1.453 3,2 e NA 127/150 L,V,T,M,A,R,N,D,Q,K,S,H,E,G,I,F,Y 73 K LYS:73:A 2.37 1 1.453,  2.658 2,1 e NA 127/150 K,N,S,D,G,L,I,V,F,Q,R,H,M,A,P,E,Y,W,T 74 K LYS:74:A 2.279 1 0.994,  2.658 3,1 e NA 127/150 K,Q,R,A,P,S,H,N,E,T,V,D,G 75 D ASP:75:A 1.863 2 0.994,  2.658 3,1 e NA 119/150 D,E,S,N,G,K,Q,T,W,A,P,R,Y,M,I,V 76 E GLU:76:A 1.228 3 0.696,  1.453 4,2 e NA 127/150 E,Q,H,S,G,R,D,K,V,C,L,N,I,A,T,Y 77 Y TYR:77:A 0.416 4 0.019,  0.696 5,4 e NA 127/150 Y,F,H,V,I,L,A,M,T,P,R 78 E GLU:78:A -0.636 7 -0.797, -0.509 8,7 e NA 127/150 E,Q,D,S,F,N,A,T 79 F PHE:79:A -0.132 5 -0.364,  0.019 6,5 b NA 127/150 F,I,V,M,Y,L,A,C,G 80 F PHE:80:A 0.665 4 0.295,  0.994 4,3 b NA 127/150 F,L,Y,M,V,D,Q,H 81 T THR:81:A -0.118 5 -0.364,  0.019 6,5 b NA 127/150 T,I,V,A,F,L,M 82 H HIS:82:A 0.266 5 -0.093,  0.473 5,4 b NA 128/150 H,Y,N,S,R,D,A,E,T,V,Q,K,C 83 L LEU:83:A 0.423 4 0.019,  0.696 5,4 b NA 129/150 L,V,F,C,S,I,T,A 84 D ASP:84:A 0.272 5 0.019,  0.473 5,4 e NA 129/150 D,A,E,S,K,N,I,M,L,Q,F,P,H,Y 85 K LYS:85:A 0.867 3 0.473,  0.994 4,3 e NA 129/150 K,S,N,P,T,A,H,E,C,I,G,V,L,R,M,Y,W 86 R ARG:86:A 1.721 2 0.994,  2.658 3,1 e NA 122/150 R,K,N,T,S,E,P,Q,A,G,M,D,H,V 87 S SER:87:A 2.523 1 1.453,  2.658 2,1 b NA 39/150 S,N,C,Y,D,A,E,G,R,Q,L,P,V,K,I,F 88 L LEU:88:A 1.944 2 0.994,  2.658 3,1 e NA 129/150 L,M,T,I,S,A,K,N,P,G,D,H,R,C,Q,E,V,F 89 P PRO:89:A 2.053 1 0.994,  2.658 3,1 e NA 129/150 P,Q,A,G,T,K,I,D,E,S,R,L,F,N,V,C 90 A ALA:90:A 1.265 3 0.696,  1.453 4,2 e NA 129/150 A,S,G,Q,N,E,D,K,R,H,L,I,T,F,V 91 L LEU:91:A 0.761 4 0.295,  0.994 4,3 b NA 129/150 L,M,V,I,F,K,T,A 92 T THR:92:A 1.573 2 0.994,  1.453 3,2 e NA 129/150 T,E,D,K,H,G,L,A,S,Y,N,Q,P,R,C,I,V,M 93 N ASN:93:A 2.202 1 0.994,  2.658 3,1 e NA 128/150 N,D,K,E,S,Q,A,V,R,T,G,H,L,I,P,F 94 I ILE:94:A 0.258 5 -0.093,  0.473 5,4 b NA 129/150 I,V,A,T,L,M,F 95 I ILE:95:A 1.143 3 0.696,  1.453 4,2 b NA 129/150 I,V,L,M,T,F,S,Q,G,D,E 96 K LYS:96:A 1.529 2 0.994,  1.453 3,2 e NA 129/150 K,Q,R,E,D,N,A,P,L,H,S,T,G,I,Y 97 I ILE:97:A 1.336 3 0.696,  1.453 4,2 e NA 129/150 I,T,C,G,S,A,D,E,N,K,V,Q,R,H,L,M 98 L LEU:98:A -0.588 7 -0.797, -0.439 8,7 b NA 130/150 L,I,V,F 99 R ARG:99:A 0.508 4 0.147,  0.696 5,4 e NA 130/150 R,K,Q,E,A,N,S,G,I,P,T,C 100 H HIS:100:A 1.418 3 0.994,  1.453 3,2 e NA 130/150 H,N,T,S,A,E,K,D,G,Q,F,R,I,P 101 D ASP:101:A 0.35 4 -0.364,  0.696 6,4 e NA 12/150 D,E,Q 102 I ILE:102:A 1.348 3 0.696,  1.453 4,2 e NA 130/150 I,T,K,Y,Q,N,R,E,S,M,D,H,C,L,V,A 103 G GLY:103:A 1.409 3 0.696,  1.453 4,2 e NA 131/150 G,S,A,E,C,V,T,I,W,M,L,N,Q,K 104 A ALA:104:A 2.463 1 1.453,  2.658 2,1 b NA 127/150 A,G,C,E,S,T,K,H,N,L,Q,D,I,V,R,P 105 T THR:105:A 1.713 2 0.994,  2.658 3,1 e NA 128/150 T,Q,H,P,S,K,N,Y,V,I,L,M,D,A,G,E,R,C,F 106 V VAL:106:A 0.438 4 0.147,  0.696 5,4 b NA 128/150 V,A,L,F,H,M,I,T,C 107 H HIS:107:A 1.218 3 0.696,  1.453 4,2 b NA 128/150 H,Q,T,N,K,S,V,L,D,M,R,E,A,G 108 E GLU:108:A 1.025 3 0.473,  1.453 4,2 e NA 129/150 E,L,V,I,M,P,T,S,F,Y,A,G 109 L LEU:109:A 1.162 3 0.696,  1.453 4,2 b NA 130/150 L,M,H,I,F,Q,N,E,D,K,V,T,R,P,A,S,Y,G,C 110 S SER:110:A 1.129 3 0.696,  1.453 4,2 b NA 131/150 S,T,A,L,D,P,G,E,R,K,H,Q,N,C 111 R ARG:111:A 1.091 3 0.473,  1.453 4,2 b NA 76/150 R,L,K,H,F,P,W,A,T,S,D,Q,G 112 D ASP:112:A 1.335 3 0.696,  1.453 4,2 e NA 76/150 D,T,N,C,K,S,E,A,G,P,V,H,F,Q 113 K LYS:113:A 1.643 2 0.994,  2.658 3,1 e NA 86/150 K,S,T,N,E,D,R,G,Q,H,C,F,V,A,L 114 K LYS:114:A 1.501 2 0.696,  1.453 4,2 e NA 88/150 K,Q,C,T,E,G,N,V,L,D,A,R,S,I,H 115 K LYS:115:A 1.448 2 0.994,  1.453 3,2 e NA 134/150 K,C,E,G,T,L,R,D,S,Q,M,N,P,V,F,I,A,H 116 D ASP:116:A 1.458 2 0.994,  1.453 3,2 e NA 137/150 D,V,N,G,A,E,T,S,K,H,R,Q,Y,W,P,M 117 T THR:117:A 0.956 3 0.473,  0.994 4,3 e NA 140/150 T,A,K,E,S,V,C,N,G,D,Q,P,L 118 V VAL:118:A 0.522 4 0.147,  0.696 5,4 b NA 143/150 V,I,G,F,M,L,T,S,A,P,N,D,C,E 119 P PRO:119:A 0.112 5 -0.193,  0.295 6,4 b NA 145/150 P,A,C,H,R,V,T,I,S,L,Q,E 120 W TRP:120:A -0.671 7 -0.847, -0.575 8,7 b NA 146/150 W,M,Q,S,I,G,D 121 F PHE:121:A -0.974 8 -1.100, -0.893 9,8 b NA 146/150 F,V,R,Y,I 122 P PRO:122:A -1.278 9 -1.338, -1.246 9,9 b s 146/150 P 123 R ARG:123:A 0.15 5 -0.093,  0.295 5,4 b NA 145/150 R,N,Y,V,T,A,K,M,Q,L,H 124 T THR:124:A -0.146 6 -0.364,  0.019 6,5 b NA 146/150 T,S,D,G,K,R,A,M,H,C,V,Q,N 125 I ILE:125:A -0.538 7 -0.692, -0.439 7,7 b NA 146/150 I,M,L,A,V,K,R,P,T 126 Q GLN:126:A 0.354 4 0.019,  0.473 5,4 e NA 146/150 Q,P,D,S,K,R,N,A,T,V,G,Y,C,W

Supplementary 3 (Continued) 127 E GLU:127:A -0.509 7 -0.692, -0.364 7,6 b NA 146/150 E,D,S,G 128 L LEU:128:A -0.971 8 -1.100, -0.893 9,8 b NA 146/150 L,A,I,T,F 129 D ASP:129:A -1.235 9 -1.318, -1.211 9,9 e f 146/150 D,Q,N 130 R ARG:130:A 1.468 2 0.994, 1.453 3,2 e NA 146/150 R,K,D,E,N,Q,L,T,S,F,M,I,H,V,C,Y,G 131 F PHE:131:A -0.135 5 -0.364, 0.019 6,5 b NA 140/150 F,Y,L,C,T,S,A,I,V,H 132 A ALA:132:A -0.209 6 -0.439, -0.093 7,5 b NA 145/150 A,L,S,I,H,T,Q,N,V,P,C,D,G,X 133 N ASN:133:A -0.125 5 -0.364,  0.019 6,5 e NA 146/150 N,S,D,R,Q,I,H,E,C,A,K,L,M,V 134 Q GLN:134:A -0.069 5 -0.282,  0.019 6,5 b NA 146/150 Q,L,H,R,S,K,N,E,V,M,T,A 135 I ILE:135:A -0.413 6 -0.635, -0.282 7,6 e NA 146/150 I,V,S,T,L,M,N 136 L LEU:136:A -0.597 7 -0.797, -0.509 8,7 e NA 146/150 L,S,V,F,T,W,M,I,Y,D 137 S SER:137:A -0.711 7 -0.847, -0.635 8,7 e NA 146/150 S,T,N,G,M,L,A,E,K,D,Q 138 Y TYR:138:A -0.458 7 -0.635, -0.364 7,6 b NA 146/150 Y,N,A,C,M,F,S,V,G,L 139 G GLY:139:A -0.642 7 -0.847, -0.509 8,7 b NA 146/150 G,V,A,D,E,T,Q 140 A ALA:140:A 0.271 5 0.019,  0.473 5,4 e NA 145/150 A,S,G,D,N,E,L,P,T,I,V,K 141 E GLU:141:A -0.219 6 -0.439, -0.093 7,5 e NA 146/150 E,F,D,R,S,H,N,A,G,L,V,T 142 L LEU:142:A -0.868 8 -1.022, -0.797 9,8 b NA 146/150 L,F,I,M,E 143 D ASP:143:A -0.522 7 -0.692, -0.439 7,7 e NA 146/150 D,E,H,S,N,K,Q,A 144 A ALA:144:A -0.066 5 -0.282,  0.019 6,5 e NA 146/150 A,V,S,H,L,E,Q,M,C,K,F,D,Y,T,P,G 145 D ASP:145:A -0.743 8 -0.893, -0.635 8,7 e f 146/150 D,C,E,G,A,N,R,T,M,K 146 H HIS:146:A -1.202 9 -1.281, -1.175 9,9 b s 146/150 H,A,Y 147 P PRO:147:A -1.066 9 -1.175, -0.981 9,8 e f 149/150 P,Q,D,V 148 G GLY:148:A -1.014 9 -1.138, -0.938 9,8 b s 149/150 G,D,S,K 149 F PHE:149:A -0.581 7 -0.746, -0.439 8,7 e NA 149/150 F,S,A,Y,H,W,C 150 K LYS:150:A 0.073 5 -0.193,  0.147 6,5 e NA 148/150 K,T,R,A,P,H,S,N,Q,G,V 151 D ASP:151:A -1.236 9 -1.318, -1.211 9,9 e f 148/150 D,N,S 152 P PRO:152:A 2.596 1 1.453,  2.658 2,1 e NA 148/150 P,A,E,V,Q,L,S,M,N,H,D,K,T,I 153 V VAL:153:A 0.562 4 0.147,  0.696 5,4 e NA 148/150 V,E,L,T,A,I,S,Q,D,G 154 Y TYR:154:A -1.154 9 -1.246, -1.100 9,9 b s 149/150 Y,I,F 155 R ARG:155:A -1.018 9 -1.138, -0.938 9,8 e f 149/150 R,H,C,Q,K,D,I 156 A ALA:156:A 1.244 3 0.696,  1.453 4,2 e NA 149/150 A,S,I,T,E,Q,K,R,L,D,N,H 157 R ARG:157:A -1.199 9 -1.281, -1.175 9,9 b s 149/150 R,A,H,G 158 R ARG:158:A -1.164 9 -1.246, -1.138 9,9 b s 149/150 R,E,K,M,Q 159 K LYS:159:A 0.337 4 0.019,  0.473 5,4 e NA 149/150 K,T,Q,M,A,S,I,E,C,R,N,G,D,L,H 160 Q GLN:160:A 1.294 3 0.696,  1.453 4,2 e NA 149/150 Q,E,V,Y,H,L,F,A,I,K,T,D,M,S,N,R 161 F PHE:161:A -0.781 8 -0.938, -0.692 8,7 b NA 149/150 F,I,V,L 162 A ALA:162:A -0.419 6 -0.635, -0.282 7,6 b NA 149/150 A,V,T,S,F,G,H,C,E,D,L,N 163 D ASP:163:A 0.49 4 0.147,  0.696 5,4 e NA 149/150 D,R,E,A,K,S,Q,N,G,T,M 164 I ILE:164:A 0.152 5 -0.093,  0.295 5,4 e NA 149/150 I,V,L,K,S,Y,F,M,A,N,H 165 A ALA:165:A -1.186 9 -1.281, -1.138 9,9 b s 148/150 A,X,S,L,P 166 Y TYR:166:A 1.468 2 0.994,  1.453 3,2 e NA 148/150 Y,F,L,H,A,M,K,T,N,R,I,E,Q,S,V 167 N ASN:167:A 0.843 4 0.473,  0.994 4,3 e NA 148/150 N,S,H,K,L,T,D,A,G,V,I,R,Q,E,F,M 168 Y TYR:168:A -0.564 7 -0.746, -0.439 8,7 b NA 148/150 Y,H,F,W 169 R ARG:169:A -0.163 6 -0.364,  0.019 6,5 e NA 148/150 R,K,S,N,Y,A,V,H 170 H HIS:170:A 0.317 4 0.019,  0.473 5,4 e NA 148/150 H,F,Y,Q,T,S,L,E,A,D,W 171 G GLY:171:A -0.953 8 -1.100, -0.847 9,8 e f 149/150 G,C,N,D 172 Q GLN:172:A 0.667 4 0.295,  0.994 4,3 e NA 149/150 Q,T,E,D,H,N,M,L,R,G,C,K 173 P PRO:173:A 1.266 3 0.696,  1.453 4,2 e NA 149/150 P,V,I,T,A,Q,K,L,R,E,Y,S,D 174 I ILE:174:A -0.726 8 -0.893, -0.635 8,7 b NA 149/150 I,L,H,V,F,M 175 P PRO:175:A -1.013 9 -1.138, -0.938 9,8 e f 149/150 P,T,S,A,E 176 R ARG:176:A 0.97 3 0.473,  0.994 4,3 e NA 149/150 R,Q,E,H,Y,P,T,K,W,V,I,S,C,D,F 177 V VAL:177:A -0.226 6 -0.439, -0.093 7,5 b NA 149/150 V,M,I,A,L 178 E GLU:178:A 0.632 4 0.295,  0.696 4,4 e NA 149/150 E,T,D,A,N,V,Q,K,S,H 179 Y TYR:179:A -1.156 9 -1.246, -1.100 9,9 b s 149/150 Y,S,F,H 180 M MET:180:A -0.651 7 -0.797, -0.575 8,7 e NA 149/150 M,T,S,I,L,N,V,R,F 181 E GLU:181:A 1.226 3 0.696,  1.453 4,2 e NA 149/150 E,K,S,N,T,P,A,I,D,Q,V,L 182 E GLU:182:A 0.477 4 0.147,  0.696 5,4 e NA 149/150 E,D,V,A,I,S,Q,N,K,T,L,R,G 183 E GLU:183:A -1.256 9 -1.318, -1.246 9,9 b s 149/150 E,S,V 184 K LYS:184:A 0.819 4 0.473,  0.994 4,3 e NA 149/150 K,I,V,R,S,T,L,N,Y,A 185 K LYS:185:A 1.295 3 0.696,  1.453 4,2 e NA 149/150 K,A,N,G,E,P,S,R,D,I,Q,T,H 186 T THR:186:A -1.13 9 -1.211, -1.100 9,9 b s 149/150 T,C,I,A,V 187 W TRP:187:A -1.199 9 -1.318, -1.138 9,9 b s 149/150 W,C 188 G GLY:188:A 1.006 3 0.473,  1.453 4,2 b NA 150/150 G,R,S,N,A,K,Q,F,E,D,T

Supplementary 3 (Continued) 189 T THR:189:A 1.545 2 0.994,  1.453 3,2 e NA 150/150 T,I,K,V,H,S,E,Q,A,L,M,R,N,D,W,Y 190 V VAL:190:A -0.433 7 -0.635, -0.282 7,6 b NA 150/150 V,I,M,T,C,L,S 191 F PHE:191:A -0.12 5 -0.364,  0.019 6,5 b NA 150/150 F,Y,A,L,W 192 K LYS:192:A 2.362 1 1.453,  2.658 2,1 e NA 149/150 K,R,Q,T,N,A,E,G,D,S,X,V,P,L,C,I 193 T THR:193:A 0.373 4 0.019,  0.473 5,4 e NA 150/150 T,E,S,N,K,Q,H,R,M,Y,G,A 194 L LEU:194:A -1.017 9 -1.138, -0.938 9,8 b s 149/150 L,G,V,M 195 K LYS:195:A 0.92 3 0.473,  0.994 4,3 e NA 149/150 K,R,T,V,S,I,N,C,M,A,H,E,Q,L,F 196 S SER:196:A 1.404 3 0.994,  1.453 3,2 e NA 149/150 S,T,K,D,R,Q,E,V,M,A,N,G,L,P 197 L LEU:197:A -0.689 7 -0.847, -0.575 8,7 b NA 150/150 L,T,M,Y,I,V,C,A,R 198 Y TYR:198:A -0.202 6 -0.439, -0.093 7,5 b NA 150/150 Y,H,F,S,L,W,M,T,I,R 199 K LYS:199:A 1.348 3 0.696,  1.453 4,2 e NA 150/150 K,N,P,S,V,A,T,Q,F,I,E,R,G,H,D 200 T THR:200:A -0.063 5 -0.282,  0.019 6,5 e NA 150/150 T,S,A,K,L,V,D,E,R,N,Q,G 201 H HIS:201:A -0.449 7 -0.635, -0.364 7,6 e NA 150/150 H,W,Y,N,K,R,L,F 202 A ALA:202:A -1.186 9 -1.281, -1.138 9,9 b s 150/150 A,R,S,F,T 203 C CYS:203:A -1.14 9 -1.246, -1.062 9,9 b s 150/150 C,T,S 204 Y TYR:204:A 1.402 3 0.994,  1.453 3,2 e NA 148/150 Y,R,K,Q,S,A,E,H,X,N,T,L,D,M,V,P 205 E GLU:205:A -1.013 9 -1.100, -0.938 9,8 e f 150/150 E,Q,H,V 206 Y TYR:206:A 0.024 5 -0.282,  0.147 6,5 b NA 149/150 Y,H,F,M 207 N ASN:207:A -0.47 7 -0.635, -0.364 7,6 e NA 149/150 N,L,I,Q,C,R,K,V 208 H HIS:208:A 1.022 3 0.473,  1.453 4,2 e NA 149/150 H,R,Y,N,K,Q,D,E,S,A,V,W,L,G 209 I ILE:209:A -0.194 6 -0.439, -0.093 7,5 b NA 149/150 I,V,M,N,H,A,G,S,T,Y 210 F PHE:210:A 0.087 5 -0.193,  0.295 6,4 b NA 149/150 F,L,I,W,K,V,P,M,C 211 P PRO:211:A 0.737 4 0.295,  0.994 4,3 e NA 149/150 P,R,T,Q,H,N,K,S,E,G,A 212 L LEU:212:A -0.044 5 -0.282,  0.147 6,5 e NA 149/150 L,I,Q,K,E,V,M,D,N,R,S 213 L LEU:213:A -0.811 8 -0.981, -0.692 8,7 b NA 149/150 L,M,F,W 214 E GLU:214:A 0.242 5 -0.093,  0.473 5,4 e NA 149/150 E,M,I,V,Q,S,T,R,H,K,L 215 K LYS:215:A 0.909 3 0.473,  0.994 4,3 e NA 150/150 K,E,D,Q,A,R,V,S,N,T,L,I,G 216 Y TYR:216:A 0.148 5 -0.093,  0.295 5,4 e NA 150/150 Y,N,T,H,Q,F,E,K,A,S,G,I 217 C CYS:217:A -0.336 6 -0.575, -0.193 7,6 b NA 150/150 C,S,F,G,D,K,A,V,Q 218 G GLY:218:A 0.219 5 -0.093,  0.473 5,4 e NA 150/150 G,A,S,E,D,K,N,L,I,V,C 219 F PHE:219:A -0.379 6 -0.575, -0.282 7,6 b NA 150/150 F,Y,V,C,L,I 220 H HIS:220:A 0.636 4 0.295,  0.696 4,4 e NA 150/150 H,R,C,N,K,Q,G,S,T,A,V,D 221 E GLU:221:A 0.067 5 -0.193,  0.147 6,5 e NA 150/150 E,Q,P,A,D,K,V,R,S 222 D ASP:222:A 0.251 5 -0.093,  0.473 5,4 e NA 150/150 D,N,Q,T,K,S,H,G,E 223 N ASN:223:A -0.341 6 -0.509, -0.193 7,6 e NA 150/150 N,Q,I,K,C,H,R,S,V,E,F,D,A 224 I ILE:224:A -0.915 8 -1.022, -0.847 9,8 b NA 149/150 I,V,L,M 225 P PRO:225:A -1.278 9 -1.338, -1.246 9,9 b s 149/150 P 226 Q GLN:226:A -1.213 9 -1.281, -1.175 9,9 b s 150/150 Q,K,S,G 227 L LEU:227:A -0.878 8 -1.022, -0.797 9,8 b NA 150/150 L,C,I,Q,A,G,M,S,V,T 228 E GLU:228:A -0.293 6 -0.509, -0.193 7,6 e NA 149/150 E,Q,D,A,K,R,G,S,N,L 229 D ASP:229:A -0.447 7 -0.635, -0.364 7,6 e NA 150/150 D,E,S,Q,A,R,K,H 230 V VAL:230:A -0.547 7 -0.692, -0.439 7,7 b NA 150/150 V,I,T,L,M,C 231 S SER:231:A -1.114 9 -1.211, -1.062 9,9 b s 150/150 S,N,T,C,D,V 232 Q GLN:232:A 1.976 2 0.994,  2.658 3,1 e NA 150/150 Q,R,N,E,Y,C,L,D,I,K,V,A,H,T,S,G 233 F PHE:233:A -1.013 9 -1.138, -0.938 9,8 b s 150/150 F,A,Y,V 234 L LEU:234:A -1.109 9 -1.211, -1.062 9,9 b s 150/150 L,S,M,C 235 Q GLN:235:A 0.124 5 -0.093,  0.295 5,4 e NA 150/150 Q,K,R,I,M,C,S,E,H,L,P 236 T THR:236:A 0.474 4 0.147,  0.696 5,4 e NA 150/150 T,S,D,E,A,G,R,Q,Y,K 237 C CYS:237:A 0.227 5 -0.093,  0.473 5,4 e NA 150/150 C,S,R,Q,W,K,T,A,H,E,N,L 238 T THR:238:A -0.957 8 -1.062, -0.893 9,8 b NA 150/150 T,S,Y 239 G GLY:239:A -1.14 9 -1.246, -1.062 9,9 e f 150/150 G,Q,K 240 F PHE:240:A -1.01 8 -1.138, -0.938 9,8 b NA 150/150 F,Y,W 241 R ARG:241:A 0.088 5 -0.193,  0.295 6,4 e NA 150/150 R,T,Q,S,I,L,C,K,V 242 L LEU:242:A -0.616 7 -0.797, -0.509 8,7 b NA 150/150 L,V,I,M 243 R ARG:243:A -1.167 9 -1.246, -1.138 9,9 b s 150/150 R,W,G,K 244 P PRO:244:A -1.231 9 -1.318, -1.211 9,9 b s 150/150 P,S 245 V VAL:245:A -0.956 8 -1.062, -0.893 9,8 b NA 150/150 V,T,S,I,A,C 246 A ALA:246:A -0.94 8 -1.062, -0.893 9,8 b NA 150/150 A,M,S,Q,G,T 247 G GLY:247:A -1.208 9 -1.318, -1.175 9,9 b s 150/150 G,N 248 L LEU:248:A -1.202 9 -1.281, -1.175 9,9 e f 150/150 L,Y,H 249 L LEU:249:A -0.968 8 -1.100, -0.893 9,8 b NA 150/150 L,I,V,T 250 S SER:250:A -1.005 8 -1.100, -0.938 9,8 b NA 150/150 S,T,P,A,L

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Supplementary 3 (Continued) 251 S SER:251:A -0.66 7 -0.797, -0.575 8,7 b NA 149/150 S,P,A,T,V,F,Q,I 252 R ARG:252:A -1.27 9 -1.338, -1.246 9,9 b s 149/150 R,I 253 D ASP:253:A -1.236 9 -1.318, -1.211 9,9 b s 149/150 D,E,H 254 F PHE:254:A -1.286 9 -1.338, -1.281 9,9 e f 149/150 F 255 L LEU:255:A -1.157 9 -1.246, -1.100 9,9 b s 149/150 L,I,M 256 G GLY:256:A -0.934 8 -1.062, -0.847 9,8 b NA 150/150 G,A,S,N,V,Y,Q,C 257 G GLY:257:A -0.664 7 -0.847, -0.575 8,7 b NA 150/150 G,A,S,C,N 258 L LEU:258:A -1.111 9 -1.211, -1.062 9,9 b s 150/150 L,I,F,V 259 A ALA:259:A -1.249 9 -1.318, -1.211 9,9 b s 150/150 A,S,V 260 F PHE:260:A -1.063 9 -1.175, -0.981 9,8 b s 150/150 F,Y,L 261 R ARG:261:A -1.2 9 -1.281, -1.175 9,9 e f 149/150 R,K,S 262 V VAL:262:A -1.049 9 -1.138, -0.981 9,8 b s 150/150 V,A,M,I,T,L 263 F PHE:263:A -1.287 9 -1.338, -1.281 9,9 b s 150/150 F 264 H HIS:264:A -0.795 8 -0.938, -0.692 8,7 b NA 150/150 H,Q,F,P,Y,S,N 265 C CYS:265:A -0.735 8 -0.893, -0.635 8,7 b NA 150/150 C,S,A,T 266 T THR:266:A -1.282 9 -1.338, -1.246 9,9 b s 150/150 T,S 267 Q GLN:267:A -1.265 9 -1.318, -1.246 9,9 b s 150/150 Q,K,L 268 Y TYR:268:A -1.246 9 -1.318, -1.211 9,9 b s 150/150 Y,K 269 I ILE:269:A -0.822 8 -0.938, -0.746 8,8 b NA 150/150 I,V,L,K,T 270 R ARG:270:A -1.269 9 -1.338, -1.246 9,9 b s 150/150 R,D 271 H HIS:271:A -1.272 9 -1.338, -1.246 9,9 b s 150/150 H,D 272 G GLY:272:A 1.395 3 0.994,  1.453 3,2 e NA 150/150 G,C,S,H,P,Q,Y,A,D,F,E,V,T,N,W 273 S SER:273:A -0.927 8 -1.022, -0.847 9,8 e f 149/150 S,A,K,T,X,N,G,V 274 K LYS:274:A 0.38 4 0.019,  0.473 5,4 e NA 150/150 K,R,N,S,Q,V,C,A,D,E,M,T 275 P PRO:275:A -1.064 9 -1.175, -0.981 9,8 e f 150/150 P,A,V,C 276 M MET:276:A 0.443 4 0.147,  0.696 5,4 e NA 150/150 M,T,L,K,F,N,W,Y,D,S,H,E,Q 277 Y TYR:277:A -1.014 9 -1.138, -0.938 9,8 e f 150/150 Y,F,H 278 T THR:278:A -1.079 9 -1.175, -1.022 9,9 e f 150/150 T,S,L,C 279 P PRO:279:A -1.066 9 -1.175, -0.981 9,8 e f 150/150 P,V,F 280 E GLU:280:A -1.285 9 -1.338, -1.281 9,9 b s 150/150 E,S 281 P PRO:281:A -1.177 9 -1.281, -1.138 9,9 e f 150/150 P,L,S 282 D ASP:282:A -1.299 9 -1.338, -1.281 9,9 b s 150/150 D 283 I ILE:283:A -0.237 6 -0.439, -0.093 7,5 b NA 150/150 I,V,T,C,A,R,M,L 284 C CYS:284:A -0.509 7 -0.692, -0.364 7,6 b NA 150/150 C,V,I,L,G 285 H HIS:285:A -1.299 9 -1.338, -1.281 9,9 b s 150/150 H 286 E GLU:286:A -1.285 9 -1.338, -1.281 9,9 b s 150/150 E,D 287 L LEU:287:A -0.89 8 -1.022, -0.797 9,8 b NA 150/150 L,V,I,F 288 L LEU:288:A -0.557 7 -0.746, -0.439 8,7 b NA 150/150 L,M,I,F,V 289 G GLY:289:A -1.268 9 -1.338, -1.246 9,9 b s 150/150 G 290 H HIS:290:A -1.272 9 -1.338, -1.246 9,9 b s 150/150 H,N 291 V VAL:291:A -0.173 6 -0.364, -0.093 6,5 b NA 150/150 V,A,C,M,I,F,L,T 292 P PRO:292:A -1.127 9 -1.246, -1.062 9,9 b s 150/150 P,A 293 L LEU:293:A -0.807 8 -0.938, -0.746 8,8 b NA 150/150 L,M,I,F 294 F PHE:294:A -0.878 8 -1.022, -0.797 9,8 b NA 150/150 F,L,Y 295 S SER:295:A -1.066 9 -1.175, -1.022 9,9 b s 150/150 S,A,C,L,G,T 296 D ASP:296:A -0.831 8 -0.981, -0.746 8,8 e f 150/150 D,E,N,Y,H,F 297 R ARG:297:A 0.093 5 -0.193,  0.295 6,4 e NA 150/150 R,P,S,H,Q,V,K,A,T 298 S SER:298:A 0.309 4 0.019,  0.473 5,4 e NA 150/150 S,A,G,K,T,D,N,E,V,Q,Y,I,L 299 F PHE:299:A -1.103 9 -1.211, -1.062 9,9 b s 150/150 F,Y,V,I 300 A ALA:300:A -1.246 9 -1.318, -1.211 9,9 b s 150/150 A,S,I 301 Q GLN:301:A -0.796 8 -0.938, -0.692 8,7 e f 150/150 Q,R,D,E,A,V,S,N,H,W 302 F PHE:302:A -1.108 9 -1.211, -1.062 9,9 b s 150/150 F,L,Y 303 S SER:303:A -1.086 9 -1.175, -1.022 9,9 b s 150/150 S,C,A,T 304 Q GLN:304:A -1.164 9 -1.246, -1.138 9,9 b s 150/150 Q,H,F 305 E GLU:305:A -0.871 8 -0.981, -0.797 8,8 b NA 150/150 E,V,D,N,Q,T,A,M,K 306 I ILE:306:A -0.735 8 -0.893, -0.635 8,7 b NA 150/150 I,V,L,T,S 307 G GLY:307:A -1.268 9 -1.338, -1.246 9,9 b s 150/150 G 308 L LEU:308:A -1.064 9 -1.175, -0.981 9,8 b s 149/150 L,M,I,V 309 A ALA:309:A -1.024 9 -1.138, -0.981 9,8 b s 149/150 A,L,S,T 310 S SER:310:A -1.241 9 -1.318, -1.211 9,9 b s 150/150 S,T,A,E 311 L LEU:311:A -1.113 9 -1.211, -1.062 9,9 b s 150/150 L,I,V

​​​​​​​

Supplementary 3 (Continued) 312 G GLY:312:A -0.943 8 -1.100, -0.847 9,8 b NA 150/150 G,A,S,L 313 A ALA:313:A -1.034 9 -1.138, -0.981 9,8 b s 150/150 A,S,T,V,F 314 P PRO:314:A -0.625 7 -0.797, -0.509 8,7 e NA 150/150 P,S,L,T,C,N,A,G,H,K,D,R 315 D ASP:315:A -0.747 8 -0.893, -0.635 8,7 e f 150/150 D,N,E,T,H 316 E GLU:316:A -0.135 5 -0.364,  0.019 6,5 e NA 150/150 E,D,S,N,A,Q,K,R,V,H 317 Y TYR:317:A -0.183 6 -0.439, -0.093 7,5 e NA 150/150 Y,F,V,M,A,D,E,S,T,Q,L,P 318 I ILE:318:A -0.522 7 -0.692, -0.439 7,7 b NA 150/150 I,V,L,C 319 E GLU:319:A 0.077 5 -0.193,  0.295 6,4 e NA 150/150 E,M,Q,K,T,L,H,S,N,D,A,R,I,V 320 K LYS:320:A -0.431 6 -0.635, -0.282 7,6 e NA 150/150 K,M,R,Q,E,H,N,S,P,L,F 321 L LEU:321:A -1.064 9 -1.175, -0.981 9,8 b s 150/150 L,F,I 322 A ALA:322:A -0.733 8 -0.893, -0.635 8,7 b NA 150/150 A,S,G,P,R 323 T THR:323:A -0.872 8 -0.981, -0.797 8,8 b NA 150/150 T,A,S,R,K,Q,N 324 I ILE:324:A 0.102 5 -0.193,  0.295 6,4 b NA 150/150 I,V,L,C,M,F 325 Y TYR:325:A -0.926 8 -1.062, -0.847 9,8 b NA 149/150 Y,F,G,C 326 W TRP:326:A -1.149 9 -1.246, -1.100 9,9 b s 149/150 W,F,V 327 F PHE:327:A -0.968 8 -1.100, -0.893 9,8 b NA 149/150 F,Y,V,W,H 328 T THR:328:A -1.104 9 -1.211, -1.062 9,9 b s 149/150 T,I,S,A 329 V VAL:329:A -0.536 7 -0.692, -0.439 7,7 b NA 149/150 V,A,I,F,L 330 E GLU:330:A -1.256 9 -1.318, -1.246 9,9 b s 149/150 E,Q,G 331 F PHE:331:A -0.875 8 -1.022, -0.797 9,8 b NA 149/150 F,Y,T 332 G GLY:332:A -1.205 9 -1.318, -1.175 9,9 b s 148/150 G,V 333 L LEU:333:A -0.482 7 -0.692, -0.364 7,6 b NA 148/150 L,I,M,V,Q 334 C CYS:334:A -0.81 8 -0.981, -0.692 8,7 b NA 148/150 C,A,T,V,S,L 335 K LYS:335:A 0.148 5 -0.093,  0.295 5,4 e NA 148/150 K,R,N,V,L,E,I,Q,M,T,S,C,G 336 Q GLN:336:A -0.823 8 -0.938, -0.746 8,8 e f 147/150 Q,E,T,D,V 337 G GLY:337:A 1.297 3 0.696,  1.453 4,2 e NA 147/150 G,D,E,Q,N,A,K,H,S,T,R 338 D ASP:338:A 0.481 4 0.147,  0.696 5,4 e NA 147/150 D,E,S,G,N,V,W,H,R,P 339 S SER:339:A 1.371 3 0.994,  1.453 3,2 e NA 147/150 S,K,D,E,A,Q,R,H,L,M,G,I,T,N 340 I ILE:340:A 1.238 3 0.696,  1.453 4,2 e NA 148/150 I,L,T,V,R,K,M,F,Y,N,A,W 341 K LYS:341:A -0.573 7 -0.746, -0.439 8,7 e NA 148/150 K,R,G,I 342 A ALA:342:A -0.871 8 -0.981, -0.797 8,8 b NA 148/150 A,V,I,C,D 343 Y TYR:343:A -0.392 6 -0.635, -0.282 7,6 b NA 148/150 Y,F,C,W,T,I 344 G GLY:344:A -1.139 9 -1.246, -1.062 9,9 b s 148/150 G,T,S 345 A ALA:345:A -1.245 9 -1.318, -1.211 9,9 b s 148/150 A,G 346 G GLY:346:A -1.141 9 -1.246, -1.100 9,9 b s 148/150 G,A,K 347 L LEU:347:A -1.063 9 -1.175, -0.981 9,8 b s 148/150 L,I,E,F 348 L LEU:348:A -1.199 9 -1.281, -1.175 9,9 b s 148/150 L,N,I 349 S SER:349:A -1.291 9 -1.338, -1.281 9,9 b s 148/150 S,H 350 S SER:350:A -1.14 9 -1.211, -1.100 9,9 e f 148/150 S,A,C,K 351 F PHE:351:A 0.089 5 -0.193,  0.295 6,4 e NA 148/150 F,Y,I,V,A,S,C,K 352 G GLY:352:A -0.815 8 -0.981, -0.692 8,7 e f 148/150 G,S,A,Q,T 353 E GLU:353:A -1.285 9 -1.338, -1.281 9,9 b s 148/150 E,P 354 L LEU:354:A -1.11 9 -1.211, -1.062 9,9 b s 148/150 L,I,M,Y 355 Q GLN:355:A 0.294 4 0.019,  0.473 5,4 e NA 148/150 Q,K,E,R,S,I,D,G,L,V,N,M,T 356 Y TYR:356:A -0.595 7 -0.746, -0.509 8,7 e NA 147/150 Y,H,W,R,V,A,N,F 357 C CYS:357:A -0.093 5 -0.364,  0.019 6,5 b NA 144/150 C,S,A,V,T 358 L LEU:358:A -0.121 5 -0.364,  0.019 6,5 e NA 144/150 L,K,V,I,M,C,S,F 359 S SER:359:A -0.422 6 -0.575, -0.282 7,6 e NA 144/150 S,T,E,N,L,Q,G,A 360 E GLU:360:A 0.829 4 0.473,  0.994 4,3 e NA 144/150 E,G,S,D,N,R,A,T,P,Q,V 361 K LYS:361:A 0.368 4 0.019,  0.473 5,4 e NA 144/150 K,T,E,Q,N,H,S,R,P,Y,V,D,G 362 P PRO:362:A -0.38 6 -0.575, -0.282 7,6 b NA 144/150 P,A,S,D,E,T,W,N 363 K LYS:363:A 0.384 4 0.019,  0.473 5,4 e NA 144/150 K,E,R,D,Q,S,N,I,C,T,P,H,V,A 364 L LEU:364:A 2.578 1 1.453,  2.658 2,1 e NA 144/150 L,Y,V,F,I,S,H,K,T,R,M 365 L LEU:365:A 1.031 3 0.473,  1.453 4,2 e NA 144/150 L,Q,K,M,R,A,Y,E,V,I 366 P PRO:366:A 1.11 3 0.696,  1.453 4,2 e NA 143/150 P,Q,A,E,D,T,V,R,K,M,I,H,G 367 L LEU:367:A -0.992 8 -1.138, -0.893 9,8 b NA 143/150 L,F,W 368 E GLU:368:A -0.039 5 -0.282,  0.147 6,5 e NA 143/150 E,D,V,N,S,I,L 369 L LEU:369:A -0.944 8 -1.100, -0.847 9,8 b NA 143/150 L,M,P,C,S,A 370 E GLU:370:A 1.508 2 0.994,  1.453 3,2 e NA 143/150 E,D,V,A,Y,F,I,S,T,K,L,Q,P,W,N 371 K LYS:371:A 1.631 2 0.994,  1.453 3,2 e NA 144/150 K,N,V,Q,R,E,I,T,S,A,H,L,M,D,W 372 T THR:372:A -0.332 6 -0.509, -0.193 7,6 b NA 144/150 T,I,M,A,C,V,R 373 A ALA:373:A -0.075 5 -0.282,  0.019 6,5 b NA 144/150 A,S,C,G,I,T,V

​​​​​​​

Supplementary 3 (Continued) 374 I ILE:374:A 2.174 1 0.994,  2.658 3,1 e NA 144/150 I,V,K,L,E,S,D,Q,T,H,N,R,M,Y,A 375 Q GLN:375:A -0.57 7 -0.746, -0.509 8,7 e NA 144/150 Q,T,E,A,H,M,C,L,N,R 376 N ASN:376:A 0.456 4 0.147,  0.696 5,4 e NA 144/150 N,E,P,K,Q,D,A,T,S,I,L 377 Y TYR:377:A -0.816 8 -0.981, -0.692 8,7 b NA 144/150 Y,C,P,L,H,S,F,N 378 T THR:378:A -0.095 5 -0.364,  0.019 6,5 e NA 143/150 T,P,N,L,I,M,R,Q,V,D,S,E,H 379 V VAL:379:A -1.02 9 -1.138, -0.981 9,8 e f 143/150 V,I,D,S,Q 380 T THR:380:A -0.848 8 -0.981, -0.746 8,8 e f 145/150 T,E,Q,M,A,N,P,L,S,Y,V 381 E GLU:381:A 0.262 5 0.019,  0.473 5,4 e NA 145/150 E,S,Q,K,C,D,G,T,A,N,R,P 382 F PHE:382:A -0.11 5 -0.364,  0.019 6,5 e NA 145/150 F,Y,P,W,M,I 383 Q GLN:383:A -1.263 9 -1.318, -1.246 9,9 b s 145/150 Q,F,N 384 P PRO:384:A 0.289 4 0.019,  0.473 5,4 e NA 145/150 P,E,D,K,N,L,S,T,C,Q,W,R,V 385 L LEU:385:A 0.58 4 0.295,  0.696 4,4 b NA 145/150 L,R,I,V,T,K,A,G,M,Q,N 386 Y TYR:386:A -1.147 9 -1.246, -1.100 9,9 b s 144/150 Y,R,F,L 387 Y TYR:387:A -0.228 6 -0.439, -0.093 7,5 b NA 144/150 Y,F,L,W,V 388 V VAL:388:A -0.255 6 -0.439, -0.093 7,5 b NA 144/150 V,I,L,F,A,Y,T,C,D 389 A ALA:389:A -0.687 7 -0.847, -0.575 8,7 b NA 144/150 A,S,T,G,L,C 390 E GLU:390:A 0.036 5 -0.193,  0.147 6,5 e NA 143/150 E,D,N,Q,K,A,X,R,F,T,S 391 S SER:391:A -0.874 8 -0.981, -0.797 8,8 e f 144/150 S,N,D,T,Q,C,R 392 F PHE:392:A -0.698 7 -0.893, -0.575 8,7 b NA 144/150 F,I,L,G,R,M 393 N ASN:393:A 0.771 4 0.295,  0.994 4,3 e NA 144/150 N,M,K,E,D,Q,G,A,L,T,S,P,I,V,F,R 394 D ASP:394:A -0.121 5 -0.364,  0.019 6,5 e NA 144/150 D,S,N,K,E,Q,V,A,C,T,G,R 395 A ALA:395:A -0.968 8 -1.100, -0.893 9,8 b NA 144/150 A,G,V,M,S 396 K LYS:396:A -0.697 7 -0.847, -0.635 8,7 b NA 144/150 K,Q,R,I,A,M,E,T 397 E GLU:397:A 1.012 3 0.473,  1.453 4,2 e NA 144/150 E,D,Q,I,A,R,N,V,M,L,S,P,T,H,K 398 K LYS:398:A -0.26 6 -0.439, -0.093 7,5 e NA 144/150 K,R,Q,L,D,M,E,P,N 399 V VAL:399:A -0.219 6 -0.439, -0.093 7,5 b NA 144/150 V,L,M,T,I,F 400 R ARG:400:A -0.307 6 -0.509, -0.193 7,6 e NA 144/150 R,K,V,I,S,L,T,M,W,Q,E 401 N ASN:401:A 1.335 3 0.696,  1.453 4,2 e NA 142/150 N,K,R,T,E,H,Q,A,S,D,L,I,G,V,M 402 F PHE:402:A -0.06 5 -0.364,  0.147 6,5 b NA 142/150 F,W,Y 403 A ALA:403:A -0.291 6 -0.509, -0.193 7,6 b NA 142/150 A,S,T,V,C,Y,G,I 404 A ALA:404:A 1.011 3 0.473,  1.453 4,2 e NA 142/150 A,S,G,H,N,K,Y,Q,D,F,L,M,E,R,T,C 405 T THR:405:A 0.611 4 0.295,  0.696 4,4 e NA 142/150 T,A,K,S,N,H,Q,R,G,D,V 406 I ILE:406:A -0.556 7 -0.746, -0.439 8,7 b NA 142/150 I,V,T,L,Q,M,F,N 407 P PRO:407:A 0.229 5 -0.093,  0.473 5,4 e NA 142/150 P,E,S,K,N,T,D,Q,R,M,C,V 408 R ARG:408:A -0.879 8 -1.022, -0.797 9,8 e f 142/150 R,K,H 409 P PRO:409:A -0.336 6 -0.575, -0.193 7,6 e NA 142/150 P,S,K,D,N,L,R,T,C 410 F PHE:410:A -0.814 8 -0.981, -0.692 8,7 b NA 142/150 F,Y,H,I,V,L 411 S SER:411:A 0.606 4 0.295,  0.696 4,4 e NA 142/150 S,T,G,M,Q,N,L,A,E,H,C,Y,F,K,V,P,I,W 412 V VAL:412:A -0.152 6 -0.364,  0.019 6,5 b NA 142/150 V,I,L,M,A,P,N 413 R ARG:413:A -0.026 5 -0.282,  0.147 6,5 e NA 142/150 R,H,T,K,Y,M,N,C,E,L,Q,A,V 414 Y TYR:414:A -0.774 8 -0.938, -0.692 8,7 b NA 142/150 Y,F,L,H 415 D ASP:415:A -0.665 7 -0.797, -0.575 8,7 b NA 142/150 D,N,E,H,R,S,I 416 P PRO:416:A 0.109 5 -0.193,  0.295 6,4 e NA 142/150 P,S,A,F,N,G,V 417 Y TYR:417:A 0.196 5 -0.093,  0.473 5,4 e NA 142/150 Y,L,F,C,H,I,V,N,Q,A,K 418 T THR:418:A -0.883 8 -1.022, -0.797 9,8 e f 142/150 T,N,I,S,G,Q,A 419 Q GLN:419:A -0.18 6 -0.364, -0.093 6,5 e NA 142/150 Q,R,H,E,A,V,K,L,C,Y,S,N,G,W,D 420 R ARG:420:A -0.659 7 -0.797, -0.575 8,7 e NA 141/150 R,S,Q,N,T,A,I 421 I ILE:421:A 0.158 5 -0.093,  0.295 5,4 b NA 140/150 I,V,M,L,A 422 E GLU:422:A -0.157 6 -0.364,  0.019 6,5 b NA 138/150 E,D,N,Q,R,K,I,M,S,W,H 423 V VAL:423:A 0.296 4 0.019,  0.473 5,4 b NA 136/150 V,I,T,F,M,L,E,A,S,Q 424 L LEU:424:A -0.302 6 -0.509, -0.193 7,6 b NA 132/150 L,I,V,D,M,T,S,P,Y 425 D ASP:425:A -0.059 5 -0.282,  0.147 6,5 e NA 131/150 D,E,N,R,K,T,Q,S,Y,P 426 N ASN:426:A 0.107 5 -0.193,  0.295 6,4 e NA 129/150 N,S,Q,R,G,K,D,A,T,E,V,H,M 427 T THR:427:A 0.383 4 0.019,  0.473 5,4 e NA 125/150 T,A,V,K,P,I,L,S,N,R,F,M,Q,Y,E 428 Q GLN:428:A 1.305 3 0.696,  1.453 4,2 e NA 124/150 Q,K,D,G,E,P,N,S,M,H,Y,R,T,A,C,L 429 Q GLN:429:A 0.121 5 -0.193,  0.295 6,4 b NA 124/150 Q,H,S,T,I,A,K,R,N,C,D,E,Y 430 L LEU:430:A 0.331 4 0.019,  0.473 5,4 e NA 124/150 L,I,V,M,T,A,C 431 K LYS:431:A 1.418 3 0.994,  1.453 3,2 e NA 124/150 K,M,R,S,V,L,I,G,E,N,Q,A,T,D,Y 432 I ILE:432:A 1.573 2 0.994,  1.453 3,2 e NA 124/150 I,N,S,D,G,H,Q,E,V,R,K,M,T,Y,A,L 433 L LEU:433:A 0.805 4 0.295,  0.994 4,3 e NA 125/150 L,M,V,A,F,Y,I,S,G,T,N 434 A ALA:434:A 0.26 5 -0.093,  0.473 5,4 e NA 125/150 A,T,M,V,L,I,S,K,W 435 D ASP:435:A 1.682 2 0.994,  1.453 3,2 e NA 125/150 D,N,G,A,K,S,T,R,Y,Q,I,H,E,C,W

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Supplementary 3 (Continued) 436 S SER:436:A 1.135 3 0.696, 1.453 4,2 e NA 125/150 S,T,C,N,D,G,E,Q,L,H,K,A,M,R 437 I ILE:437:A 0.271 5 -0.093, 0.473 5,4 e NA 125/150 I,S,L,V,M 438 N ASN:438:A 0.717 4 0.295, 0.994 4,3 e NA 124/150 N,K,S,G,H,I,R,E,Q,C 439 S SER:439:A 0.935 3 0.473,  0.994 4,3 e NA 123/150 S,N,G,C,H,Q,T,R,Y,D,E,A,L,I 440 E GLU:440:A -0.31 6 -0.509,-0.193 7,6 e NA 123/150 E,M,D,Q,N,H 441 I ILE:441:A 0.783 4 0.295, 0.994 4,3 e NA 122/150 I,V,M,L,Y,F,T,N 442 G GLY:442:A 1.237 3 0.696, 1.453 4,2 e NA 122/150 G,S,E,H,D,M,Q,A,N,F,C,K,L,T,R 443 I ILE:443:A 1.011 3 0.473, 1.453 4,2 e NA 122/150 I,K,C,L,V,M,T,E,R,A,S,N,H,Q 444 L LEU:444:A -0.733 8 -0.893, -0.635 8,7 e f 121/150 L,C,I,V 445 C CYS:445:A 0.949 3 0.473, 0.994 4,3 e NA 120/150 C,S,V,E,Q,L,T,I,M,H,A,G,N,R,F 446 S SER:446:A 1.285 3 0.696, 1.453 4,2 e NA 119/150 S,N,E,Q,D,T,G,H,F,K,L,A,C,R 447 A ALA:447:A -0.92 8 -1.062, -0.847 9,8 e f 119/150 A,S,T,V,I 448 L LEU:448:A -0.169 6 -0.439, 0.019 7,5 e NA 119/150 L,F,V,I,M,A 449 Q GLN:449:A 1.824 2 0.994, 2.658 3,1 e NA 117/150 Q,R,K,T,S,D,E,A,H,M,G,N 450 K LYS:450:A -0.226 6 -0.439, -0.093 7,5 e NA 105/150 K,R,Q,T,A,N,V,Y 451 I ILE:451:A 0.882 3 0.473, 0.994 4,3 e NA 89/150 I,N,L,V,F,M 452 K LYS:452:A -0.747 8 -1.022, -0.575 9,7 e f 18/150 K,R * Below the confidence cut-off - The calculations for this site were performed on less than 6 non-gaped homologue sequences, or the confidence interval for the estimated score is equal to- or larger than- 4 color grades.

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