Structural Roles of the Amino Acids

Hydrophobic “H” vs polar “P” : is the most important parameter
     “HP” pattern in sequence determines approx. 3D fold, putting most H in, P out
     “H” : function of Hydrophobic surface area (but Cys also strongly buried)
     “P” : function of charge, H-bonding, polarizability (but Pro out, forming corners)
     alternating “HP” favors ↑↓ β; 3.5 period favors α helix; a run of “P” favors turns;
     long run of “H” favors transmembrane; short run of “H” favors ↑↑ β

Size, shape, & flexibility of sidechain
     Mainchain flexibility: Gly > Ala (and others) > branched Cβ > Pro > SS
         Entropy mutants (native vs unfolded): SS, A → P , G → A
     Sidechain degrees of freedom: Hydrophobics <= 2 chi’s (χ) (except Met 3))
         many Polars have more, esp/ Lys & Gln very loose
     Aromatics (FYWH): big & flat, help constrain packing
         slightly + on edge, - on face, more often perpendicular than stacked
     Pro: not aromatic, not flat; puckers up or down at Cγ
         ring constrains φ near -60°; good at turns; can do α , but bends helix
     Ile, Thr sidechains handed: long arm, or Og, on “left” side (arms in front of body)
     Sidechains “rotameric”, i.e. few preferred conformations; Ctetr near staggered
         Sidechain angles: χ1, χ2 , etc. dihedrals (χ4 max, for Lys & Arg)
         for bonds between tetrahedral carbons, staggered >> eclipsed
         overall, a few well-defined sidechain conformations are good: rotamers
         [only 2 good ( 4 more OK) for Leu; 13 for Met with 3 χ angles and no branches]

Secondary-structure preferences
     Loop, turn, coil : Gly, Ser, Asn, Pro, & charges best; Hydrophobics poor
     Beta : branched Cβ’s best (Val, Ile, Thr); Pro, Asn worst
     Helix : in middle: Ala, Leu, Met, Gln best; Pro worst
         near beginning – charge good (Asp, Glu); near end + charge good (Lys, Arg, His)
         N-cap : Asp, Asn, Ser, Thr best (sc H-bond to mc NH of N-cap +3 or +2)
         N-cap +1 : Pro best
         C-cap : Gly best (usually has +φ value)
         pair of touching Hydrophobics often bracket N or C caps

Pair comparisons (What is a conservative replacement?)
     Arg ordered, H-bonded (5-planar O’s),
          vs Lys often disordered, helps solubility
     Leu one of best for helix,
          vs Ile one of best for β-sheet
     Asn backbone mimic, best non-Gly for +φ conf.; strong pref.s; amide constrained
          vs Gln “plain vanilla” residue: good α, OK most places; amide very free
         Asn one of best N-caps, Gln is worst
         Gln one of best at specific DNA base H-bonds, Asn too short & wrong angles

Multiple roles: distinguish by replacement pattern in aligned sequences
     Arg: +charge (sub=Lys); oriented H-bonds (sub=Gln); Hydrophobic (sub=Tyr, Leu, Ile)
     Gly: flexibility (sub=Ser); small size (sub=Ala or none); +φ conf. (sub=Asn)
     His: titrates near pH 7 (no sub); +charge (sub=Lys, Arg); H-bonds (sub=Gln, Asn);
         metal ligand (sub= Cys, Asp, Glu)
     Cys: buried SH (sub=Hydrophobics); SS (sub=Hydrophobics, rarely);
         metal ligand (sub=His, Asp, Glu, rarely)