DERIVATION OF CLASS-II FORCE-FIELDS - V - QUANTUM FORCE-FIELD FOR AMIDES, PEPTIDES, AND RELATED-COMPOUNDS

As the field of biomolecular structure advances, there is an ever-grow ing need for accurate modeling of molecular energy surfaces to simulat e and predict the properties of these important systems. To address th is need, a second generation amide force field for use in simulations of small organics as well as proteins and peptides has been derived. T he critical question of what accuracy can be expected from calculation s in general, and with this class ii force field in particular, is add ressed for structural, dynamic, and energetic properties. The force fi eld is derived from a recent methodology we have developed that involv es the systematic use of quantum mechanical observables. Systematic ab initio calculations were carried out for numerous configurations of 1 7 amide and related compounds. Relative energies and first and second derivatives of the energy of 638 structures of these compounds resulte d in 140,970 ab initio quantum mechanical observables. The class II pe ptide quantum mechanical force field (QMFF), containing 732 force cons tants and reference values, was parameterized against these observable s. A major objective of this work is to help establish the role of anh armonicity and coupling in improving the accuracy of molecular force f ields, as these terms have not yet become an agreed upon standard in t he ever more extensive simulations being used to probe biomolecular pr operties. This has been addressed by deriving a class I harmonic diago nal force field (HDFF), which was fit to the same energy surface as th e QMFF, thus providing an opportunity to quantify the effects of these coupling and anharmonic contributions. Both force field representatio ns are assessed in terms of their ability to fit the observables. They have also been tested by calculating the properties of 11 stationary states of these amide molecules. Optimized structures, vibrational fre quencies, and conformational energies obtained from the quantum calcul ations and from both the QMFF and the HDFF are compared. Several strai ned and derivatized compounds including urea, formylformamide, and but yrolactam are: included in these tests to assess the range of applicab ility (transferability) of the force fields. It was found that the cla ss II coupled anharmonic force field reproduced the structures, energi es, and vibrational frequencies significantly more faithfully than the class I harmonic diagonal force field. An important measure, rms ener gy deviation, was found to be 1.06 kcal/mol with the class II force fi eld, and 2.30 kcal/mol with the harmonic diagonal force field. These d eviations represent the error in relative configurational energy diffe rences for strained and distorted structures calculated with the force fields compared with quantum mechanics. This provides a measure of th e accuracy that might be expected in applications where strain may be important such as calculating the energy of a system as it approaches a (rotational) barrier, in Ligand binding to a protein, or effects of introducing substituents into a molecule that may induce strain. Simil ar results were found for structural properties. Protein dynamics is b ecoming of ever-increasing interest, and, to simulate dynamic properti es accurately, the dynamic behavior of model compounds needs to be wel l accounted for. To this end, the ability of the class I and class II force fields to reproduce the vibrational frequencies obtained from th e quantum energy surface was assessed. An rms deviation of 43 cm(-1) w as achieved with the coupled anharmonic force field, as compared to 10 5 cm(-1) with the harmonic diagonal force field. Thus, the analysis pr esented here of the class II force field for the amide functional grou p demonstrates that the incorporation of anharmonicity and coupling te rms in the force field significantly improves the accuracy and transfe rability with regard to the simulation of structural, energetic, and d ynamic properties of amides. (C) 1998 John Wiley & Sons, Inc.