Supplementary Information for
Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides and
their analogs
Robin Chaudret, Jerry M. Parks and Weitao Yang
Contents
a. General dihedral behavior
b. Dihedral angles in additional molecules
c. Bond Dissociation Error table
d. Full Gaussian reference
a. General dihedral behavior
In this section we discuss the differences in dihedral angles between molecules
containing pseudobonds (PsMols) and the corresponding standard reference molecules
(StdMols). In general, performance of the pseudobond method for geometric quantities
including bonds, angles and dihedrals is quite good. However, some significant deviations are
found for some of the dihedrals, evident as off-diagonal points in Figure S1. Here, we review
the reasons explaining such behavior. The RMSE for the Tot pseudobond (parameters
optimized against the total training set) is 9.3° (maximum errors are -31.5° and 35.1°. One
points near (-180º,180º) represents only a small modification of a dihedral with values close
to 180º. The largest errors often come from the rotation of highly flexible groups such as the
2’ or 3’ hydroxyls or the phosphates. In addition, neglecting inclusion of the MM subsystem
or the rotation of some of its substituent atoms induces a relaxation of the ribose sugar ring
because the potential energy surface is very flat. However, such flexibility of the phosphate
group is not expected to occur in a more realistic QM/MM system where it would be bonded
either to another nucleic acid or to a diphosphate group, for example in ATP.
200
150
Pseudobond
100
50
0
-200
-100
-50
0
100
200
-100
-150
-200
Standard
Figure S1: Correlation of dihedrals in molecules containing pseudobonds (PsMol) and
standard molecules (StdMol) for the Total test set.
b. Dihedral angles in additional molecules
The dihedral RMSE values were computed individually for each PsMol and were
found to be quite low (1.9-3.3 degrees) for clofarabine, emtricitabine, tenofovir, and triglycine
polypeptide (Table S1). However, the dihedral RMSE is large for acyclovir (14.1 degrees).
The same reasons as for the larger deviations in the angles (see main text) can be used to
explain the large deviations in the dihedrals. For the acyclovir StdMol, a hydrogen bond is
present between the hydroxyethoxymethyl tail and a guanosyl nitrogen atom, which forms an
effective nine-membered ring and therefore restrains the conformation slightly (Figure S2-a).
However, the PsMol lacks the nucleobase completely so geometry optimization of the PsMol
alters the conformation of the hydroxyethoxymethyl tail of acyclovir significantly. Full
QM/MM optimization of acyclovir, which includes the guanosyl group explicitly in the MM
subsystem leads to a structure that more closely matches the StdMol (Figure S2-b). If the
rmse of the QM/MM minimization is not better (18.1º), most of the error comes from the
rotation of the hydroxyl hydrogen, removing it from the calculation decreases the rmse to 4.8º
for the QM/MM calculation but only to 13.2º for the PsMol. This shows that the heavy atoms
position aremuch better conserved during QM/MM minimization of the whole molecules than
during QM minization of the PsMol.
Table S1: RMS errors for dihedral angles in acyclovir, clofarabin, emtricitabine, ribavirin and
tenofovir.
Molecule
Dihedral RMSE(°)
aciclovir
14.1
clofarabine
3.3
emtricitabine
3.2
tenofovir
3.1
tetraglycine
1.9
Figure S2 : Representation of (a) the optimized (StdMol) structure of acyclovir and (b) a
comparison of the traces of the StdMol (gold), PsMol (blue) (b.) and QM/MM-optimized
molecule (purple). The PsMol does not contain any MM atoms so the guanosyl base is absent.
In (a), the intramolecular hydrogen bond between the guanosyl group and the terminal
hydroxyethoxymethyl group is shown in red.
c. Bond Dissociation Errors table
Table S2: Bond Dissociation (BD) energies and errors in kcal/mol and BD errors in %age of
the BD energies for the total training set molecules.
Molecule
ADE
THY
GUA
CYT
URA
rADE
rTHY
rGUA
rCYT
rURA
BD Energy BD Error
BD Error
(kcal/mol) (kcal/mol) (% BD Energy)
346.4
9.7
2.8
346.4
8.8
2.5
346.4
16.6
4.8
346.5
6.8
2.0
346.4
9.6
2.8
421.7
9.6
2.3
421.7
1.7
0.4
421.6
16.6
3.9
421.7
2.5
0.6
421.7
2.7
0.6
d. Full Gaussian09 reference
Gaussian 09, R. A., Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg,
J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro,
F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi,
M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009.