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Knowledge-based potential for partial covalent interactions (PCI-
KBP)
Steven Combs
1
Partial Covalent Interactions (PCI)
• An interaction between an e-
deficient atom to a slightly positive atom
– Cation-pi
– Pi-pi
– Salt bridge
– Hydrogen Bonds
2
Cation-π π - π
Hydrogen Bonds / Salt bridges
Placement of Orbitals on Atoms Allows for an Accurate Description of PCIs
3
Orbital Type Name
Hybridization Atom Type Example Picture
C.pi.sp2 sp2aroCCOO
CNH2
Tyr, Trp, PheAsp, GluAsn, Gln
N.pi.sp2 sp2
NtrpNargNhis
NH20
TrpArgHis
Asn, Gln
N.p.sp2 sp2 Nhis His
O.pi.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp3 sp3 OH Ser, Thr, Tyr
S.p.sp3 sp3 S Cys, Met
θ H
X’
H
Orbital Placement Improves Sharpness and Depth of Energy Wells
Cation-π
θ Hpol
X’ 4
Rosetta Orbital Type Name
Rosetta Orbital Type
Hybridization Rosetta
Atom Type Picture
C.pi.sp2 pi sp2 aroC COO CNH2
-1.50
-1.20
-0.90
-0.60
-0.30
0.00
0.05
0.55
1.05
1.55
2.05
2.55
3.05
3.55
180:
120:
90:
An
gleθ
Distance δH-Y’(Å)
Ener
gy (
no
t sc
aled
)
0:
-1.50
-1.20
-0.90
-0.60
-0.30
0.00
0.0
5
0.5
5
1.0
5
1.55
2.0
5
2.5
5
3.0
5
3.5
5
Orbital Placement Improves Sharpness and Depth of Energy Wells
π - π
180:
120:
90:
An
gleθ
Distance δH-Y’(Å)
θ Haro
X’
5
Rosetta Orbital Type Name
Rosetta Orbital Type
Hybridization Rosetta
Atom Type Picture
C.pi.sp2 pi sp2 aroC COO CNH2
Ener
gy (
no
t sc
aled
)
0:
Orbital Placement Improves Sharpness and Depth of Energy Wells
6
-3.00
-2.70
-2.40
-2.10
-1.80
-1.50
-1.20
-0.90
-0.60
-0.30
0.00
0.05
0.55
1.05
1.55
2.05
2.55
3.05
3.55
θ Hpol
X’
180:
120:
90:
An
gleθ
Distance δH-Y’(Å)
Ener
gy (
no
t sc
aled
)
0:
Rosetta Orbital Type Name
Rosetta Orbital Type
Hybridization Atom Type Picture
O.p.sp2 p sp2 ONH2 OOC
The PCI-KBP Is Divided into Two Scoring Terms
Orbital Type Name
Hybridization Atom Type Example Picture
C.pi.sp2 sp2aroCCOO
CNH2
Tyr, Trp, PheAsp, GluAsn, Gln
N.pi.sp2 sp2
NtrpNargNhis
NH20
TrpArgHis
Asn, Gln
N.p.sp2 sp2 Nhis His
O.pi.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp3 sp3 OH Ser, Thr, Tyr
S.p.sp3 sp3 S Cys, Met
orbitals_hpol
orbitals_haro
7
Weights Used During Optimization
Free Removed
8
Score Term Description
Fa_atr Attractive portion of LJ
Fa_rep Repulsive portion of LJ
Fa_sol Implicit solvation potential
Fa_intra_rep Intra-residue repulsion
Pro_close Close the proline ring
Hbond Hydrogen bond potential
Dslf Disulphide potential
Rama Phi-psi angles in ramachandran plot
Fa_dun Dunbrack rotamer library
P_aa_pp Probability of an amino acid given phi-psi angle
hpol, haro, sol pair, hbond_sc
hbond_sc, pair, sol
hpol, haro, bb_hpol, sol
pair, hbond_sc, hbond_bb_sc
1.
2.
3.
8
Score12
Benchmark Set-up
• Dataset from et al Grishin 2001
• Better than 1.8A
• 100-500 Residues
• Monomeric
• No ligands
• Complete Side chains
9
Introduction of Partial Covalent Interactions within Rosetta Improves
Protein Metrics
Location % SR
Buried 63
Surface 31
Overall 46
Location % SR
Buried 65
Surface 35
Overall 49
Orbitals
Location % SR
Buried 69
Surface 36
Overall 52
Score 12 Optimized Score12
Location % PSSM
Buried 72
Boundary 73
Surface 73
Overall 72
Location % PSSM
Buried 77
Boundary 74
Surface 76
Overall 76
Location % PSSM
Buried 78
Boundary 78
Surface 77
Overall 78
Packstats 0.68 Packstats 0.63 Packstats 0.60
Identifying non-Classical PCIs Sulfur-Aromatic
11
Orbital Type Name
Hybridization Atom Type Example Picture
C.pi.sp2 sp2aroCCOO
CNH2
Tyr, Trp, PheAsp, GluAsn, Gln
N.pi.sp2 sp2
NtrpNargNhis
NH20
TrpArgHis
Asn, Gln
N.p.sp2 sp2 Nhis His
O.pi.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp3 sp3 OH Ser, Thr, Tyr
S.p.sp3 sp3 S Cys, Met
180:
120:
90:
An
gleθ
Distance δH-Y’(Å)
0:
0 2 4
Identifying non-Classical PCIs Anion-Pi
12
Orbital Type Name
Hybridization Atom Type Example Picture
C.pi.sp2 sp2aroCCOO
CNH2
Tyr, Trp, PheAsp, GluAsn, Gln
N.pi.sp2 sp2
NtrpNargNhis
NH20
TrpArgHis
Asn, Gln
N.p.sp2 sp2 Nhis His
O.pi.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp2 sp2ONH2OOC
Asn, GlnAsp, Glu
O.p.sp3 sp3 OH Ser, Thr, Tyr
S.p.sp3 sp3 S Cys, Met
180:
120:
90:
An
gleθ
Distance δH-Y’(Å)
0:
0 2 4
Conclusions
• Orbital placement allows for accurate description of residue interactions
• PCI-KBP can perform as well as score12
• New interactions are captured by PCI-KBP
13
Future Work
• Extend PCI-KBP to ligands/DNA/RNA
• Improve geometry of interactions
• Fix little bugs/memory leaks/speed
14
Acknowledgements Meiler Lab Sam Deluca Gordon Lemmon Nils Woetzel Kuhlman Lab Andrew Leaver-Fay Matt O’Mera
Committee Dr. Brian Bachmann Dr. Richard Armstrong Dr. Jens Meiler Dr. Martin Egli