Protein
Parametrizations
Ladislav Bartoš
March 29, 2021
FB810/C9926 Course
Mar 29, 2021 Ladislav Bartoš
Molecular Mechanics
2
●
what should the parameters in the equations be?
●
simulations should match the reality easier said
than done
Mar 29, 2021 Ladislav Bartoš
Force Field Families
3
AMBER
ff94 ff96
ff99
ff99SB
ff99SB-ILDN
ff99SB*-ILDN
ff99SB-ILDN-φ
ff99SB-ILDN-NMR
ff03
ff03*
ff03W
ff03WS
…
CHARMM
C22
C22*
C27
C36
…
GROMOS
53a6
53a5
43a1
43a1p
…
OPLS-AA
OPLS-AA/M
Which force
field to use?
ff99SB*
Mar 29, 2021 Ladislav Bartoš
Benchmark #1
4
●
Lindorff-Larsen et al., 2012
●
simulations of two folded proteins vs. NMR data
→ ff03, ff03*, C22, OPLS-AA
●
temperature dependent structural properties of proteins
→ C27, ff03 overstabilize helical structures
→ ff99SB-ILDN underestimates the stability of helices
●
folding of α-helical & β-sheet proteins
→ ff03, C22, C27, OPLS-AA
●
best force fields? → ff99SB*-ILDN & C22*
Mar 29, 2021 Ladislav Bartoš
Benchmark #1: Force Fields
4
AMBER
ff94 ff96
ff99
ff99SB
ff99SB-ILDN
ff99SB*-ILDN
ff99SB-ILDN-φ
ff99SB-ILDN-NMR
ff03
ff03*
ff03W
ff03WS
…
CHARMM
C22
C22*
C27
C36
…
GROMOS
53a6
53a5
43a1
43a1p
…
OPLS-AA
OPLS-AA/M
ff99SB*
Mar 29, 2021 Ladislav Bartoš
Benchmark #2
5
●
Beauchamp et al., 2012
●
simulations of peptides compared with a large number
of NMR measurements
●
ff99SB-ILDN-φ & ff99SB-ILDN-NMR
→ calculation errors ≈ experimental uncertainty
●
new force fields:
> Amber: ff14SB, ff19SB
> CHARMM: C36
Mar 29, 2021 Ladislav Bartoš
Benchmark #2: Force Fields
5
AMBER
ff94 ff96
ff99
ff99SB
ff99SB-ILDN
ff99SB*-ILDN
ff99SB-ILDN-φ
ff99SB-ILDN-NMR
ff03
ff03*
ff03W
ff03WS
…
CHARMM
C22
C22*
C27
C36
…
GROMOS
53a6
53a5
43a1
43a1p
…
OPLS-AA
OPLS-AA/M
ff99SB*
Mar 29, 2021 Ladislav Bartoš
Intrinsically Disordered Proteins
6
●
intrinsically disordered = no fixed tertiary structure
●
problem 1: capturing disordered regions
●
problem 2: capturing both the folded & disordered regions
●
CHARMM: C36 → C36m Amber: ff99SB →
ff99SB-disp
Mar 29, 2021 Ladislav Bartoš
Conclusion
●
know the limitations of your force field
●
choose a force field appropriate for your system
●
when in doubt:
> simulate the system twice with different force fields
Internal dynamics of α-helical protein?
> FF underestimating α-helix stability
A system with no α-helices?
> FF underestimating α-helix stability
7