computer modeling in molecular biology.pdf

7 Major Histocompatibility Complex Class I Protein-Peptide Interactions 205mediated through solvent. Position P1 of the peptide only makes one hydrogen bondingcontact with a side chain from HLA-B27, using the terminal NH to bond tothe C=O of Glu163. Glu163 also makes a hydrogen bond to Arg62, a residue whichis found in all HLA-B and HLA-C alleles except for HLA-B57 and HLA-B58, andhas two potential contacts to the water molecule TIP465 which interacts with themain chain NH of position P4 of the peptide. Arg62 makes two additional contactsto the peptide at the main chain C=O of position P2. Glu63 aids this interactionby interacting itself with the terminal NH of Arg62 holding the guanidinium groupof the arginine side chain in a plane perpendicular to the P-sheet, and aligning it sothat it may interact with good geometry with both the peptide and its salt bridgepartner in the a2 a-helix, Glu163. The interaction of the arginine side chain at P1with the strong salt bridge which holds the a1 and a2 helices together, appears tostrengthen the interaction of the peptide with the protein and helps to stabilise theprotein itself. This salt bridge is not found in all HLA-B alleles but can be predictedto form in certain members of the HLA-B7, HLA-B13, HLA-B40, HLA-B47 andHLA-B48 families in addition to HLA-B27. Amongst the HLA-A and HLA-C allelesHLA-A*2501, HLA-A*2601, HLA-A*4301, HLA-A*6601, HLA-Cw*0201 and HLA-Cw*0202 also possess the potential for this stabilising salt bridge. Glu63 makes agood hydrogen bond to the main chain NH of ArgP2 furnishing the backbone ofthis position with an excellent network of contacts which aid the stability of thearginine side chain in the P2 pocket. The hydrogen bonding contacts within the P2pocket are identical to those which have been discussed previously [3]. The mainchain NH of the isoleucine residue at position P3 of the peptide hydrogen bonds withthe side chain hydroxyl group of Tyr99, a residue conserved in all classical HLA classI sequences except for HLA-Cwl and HLA-A*0207 which have a cysteine and HLA-Bw41, HLA-A*0210, and HLA-Aw24 which have a phenylalanine. The main chainC=O of P3 interacts with TIP464 which is part of the complex bed of watermolecules which support the flexible and largely un-chelated central bulge of thepeptide [3-51. This water molecule interacts with TIP457, which is part of thegeneral net of water molecules, and TIP456 which interacts with ArgP2 of the peptideand His9 and Sr99 of the heavy chain as part of the planar hydrogen bondingnetwork in the P2 binding pocket. The main chain NH of P4 hydrogen bonds toTIP465 which mediates an interaction to the side chain of Glu163. Both the mainchain carbonyl of P4 and the main chain amide of P5 are devoid of any contacts,and the main chain carbonyl of P5 interacts via TIP459 with the general solventfield. The aspartic acid side chain of P5 makes no contacts to the MHC but is pointingdirectly upwards, perpendicular to the P-sheet, probably facing the T-cell receptorin the in vivo complex. The main chain of LeuP6 makes no hydrogen bondingcontacts to the MHC and the main chain of IleP7 interacts only with the solvent fieldinside the cleft. The main chain amide of PC-1 (P8) does not interact with either theMHC or solvent, and the main chain carbonyl interacts with the pyrrole NH ofTrp147 as observed in the high resolution HLA-B*2705 [3] and HLA-Aw68 [16, 171