Subject: Re: CCL:MOLECULAR MECH QUESTIONS

From: Per-Ola Norrby <[email-masked]>
Date: Thu, 18 Dec 1997 09:42:32 +0100

On 1997  Dec 17, E. Lewars wrote:

>Molecular mechanics (MM) gives strain energies.  Questions:
>
>Are these statements correct ? :
>
>(1)  Strain energy differences are enthalpy differences (deltaH).
>     (If true, then deltaH under what conditions--zero K?  room temp? I
>suppose
>     it depends on the parameterization  of the force field: k_stretch etc
>      might have been for, say, 0 K...?)

	Close enough for practical purposes.  If you're a purist, read on
below.

>(2)   MM programs that calculate frequencies can in principle calculate
>      entropies and thus free energies.

	True.  You'll have to be very careful though, using the harmonic
approximation for a low mode might give serious errors.  This problem is
not unique to MM, most QM programs also use the harmonic approximation.  A
few programs (both QM and MM) are smart enough to treat free rotations
separately, but I don't know of any simple approximations that gives
accurate entropies when you deal with intermediate modes (say, 10-50 cm-1,
maybe even wider).

	For the purists, an elaboration on (1):
	Molecular mechanics energies will in principle give back the type
of energies they are parameterized with.  A few force fields, like CFF95
and MMFF, were parameterized from ab initio data, and will thus yield
potential energies at the bottom of the energy well.  The difference
between this number and the enthalpy at zero K is the zero point energy,
and in energy DIFFERENCES this number can frequently be neglected.  Many
force fields (for example, the MM2/MM3/MM4 programs) instead uses
enthalpies directly, including the vibrational contribution into the
potential energy surface.  This gives some tricky theoretical problems when
you add a vibrational analysis to something that already includes a part of
the vibratinal contribution, especially when you move away from stationary
points.  In practice, this is ignored, and all molecular mechanics force
fields are treated as if they yield a potential energy.

	Note that enthalpies (and free energies and entropies) in principle
are properties that depend on all contributing geometries within a
potential energy well.  Thus,  you cannot really talk about the enthalpy of
a single point on the potential energy surface.  From a potential energy
surface, you may calculate the enthalpy for each well, but you cannot go
backwards and deduce a potential energy surface from the enthalpies (other
than postulating a PES and see if it gies a correct enthalpy, of course).

	One more note: the programs MM3 and MM4 have partially overcome the
problem by an end-of-calculation analysis that converts the vibrationally
averaged properties to what would be predicted from several different types
of experiments (including, the "bottom-of-the-well" properties from ab
initio).  This seems to work well at least for bond lengths.  I'd be
interested to know if some better theoretician than me can find out if you
can really go back to a true potential energy surface though.

	Holiday greetings from

	Per-Ola Norrby

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
 *  Per-Ola Norrby, Associate Professor
 *  The Royal Danish School of Pharmacy, Dept. of Med. Chem.
 *  Universitetsparken 2, DK 2100 Copenhagen, Denmark
 *  tel. +45-35376777-506, +45-35370850    fax +45-35372209
 *  Internet: [email-masked], http://compchem.dfh.dk/