The partitioning of the overall molecular charge distribution into ato
m centered monopole charges, while quantum mechanically ill-defined, i
s nevertheless a technique which finds applications in several broad c
lasses of chemical problems. Charges derived from fits to electrostati
c potentials have an intuitive appeal since, in principle, these could
be derived from either theoretical or experimental data. It has been
noted, however, that such potential derived charges can be conformatio
nally dependent in ways that do not appear to reflect the changes in t
he molecular wavefunction. Both the algorithm used for selecting point
s at which the molecular electrostatic potential will be fit and the d
ensity of points used in the fit have been suggested to influence the
resultant charges. Recently [Stouch TR, Williams DE (1992) J Comp Chem
13: 622-32; Stouch TR, Williams DE (1993) J Comp Chem 14: 858-66] it
has been noted that numerical difficulties may make it impossible to f
it all the atomic charges in a molecule. Singular value decomposition
(SVD) of the linear least squares matrices used in fitting atom based
monopoles to molecular electrostatic potentials provides a tool for ev
aluating the integrity of the calculated charges. Based on the SVD ana
lysis for a selected group of molecules we have noted particularly tha
t increasing the molecular size reduces the fraction of charges which
can be validly assigned. Users of PD derived charges, especially those
who are using those charges for tasks other than reproduction of the
MEP, should be aware that there is a high probability that a significa
nt portion of those charges are statistically unreliable. Therefore, c
harges in many biological molecules, such as sugars, prove to be diffi
cult to obtain by potential derived (PD) methods such as CHELP or CHEL
PG. Results from the SVD can be used to both assess PD charges and to
generate an improved, albeit incomplete, set. Improved PD fits are pre
sented for a series of simple saccharides.