Molecular mechanics force fields MMFFs

For much more flexible molecules than 18, DFT PES scans can be impractical. Currently, for such molecules conformational analysis is most efficiently carried out in two stages first, Monte Carlo searching using a molecular mechanics force field (MMFF) determines the stable conformations predicted by the MMFF second, these conformations are re-optimized using DFT. For example, conformational analysis of the... 

Molecular mechanical force fields (MMFFs) were first proposed in the 1940s to study steric effects of organic molecules and were extended to model biomolecular systems by Lifson and coworkers in the 1960s.Since that time, significant progress has been made, and a number of force fields have been developed that can be used to provide excellent quantitative interpretation of experimental observations. ... 

Molecular mechanical force fields (MMFFs) have been successfully used to model condensed-phase and biological systems for a... 

In this chapter, we study small-molecule conformations and energetics using different levels of theory (molecular mechanics force field, semiempirical, and QM) to reproduce conformations found in the CSD. While our eventual goal is to predict the actual crystal form, here we focus on the conformation of the small molecule, with only one example to show the use of an accurate conformation to be used in the prediction of the solid form. We study two particular interaction types that tend to be poorly reproduced with standard force fields close intramolecular S--0 interactions and halogen X O interactions however, the methods presented here are generalizable to other interactions. We study two heavily used small-molecule force fields, the MMFFs variant of MMFF [38, 39] and the OPLS 2005 version of OPLS [16, 40], and demonstrate how modifications to the latter can improve the generation of structures with low RMSD relative to small-molecule crystal structures. 

Inadequate availability of experimental data can considerably inhibit the development of improved energy functions for more accurate simulations of energetic, structural, and spectroscopic properties. This has led to the development of class II force fields such as CFF and the Merck Molecular Force Field (MMFF), which are both based primarily on quantum mechanical calculations of the energy surface. The purpose of MMFF, which has been developed by Thomas Halgren at Merck and Co., is to be able to handle all functional groups of interest in pharmaceutical design. 

Over the past years the search for more reliable discrimination of L/M relative steric size and theoretical prediction of the preferred interporphyrin helicity of the host—guest complex has led to the development of molecular mechanics calculations protocol using the Merck Molecular Force Field (MMFF) approach coupled to Monte Carlo-based conformational analysis.57... 

This chapter describes the basis of molecular mechanics models and introduces the SYBYL and MMFF force fields. It also compares and contrasts molecular mechanics and quantum chemical models. 

Molecular mechanics models differ both in the number and specific nature of the terms which they incorporate, as well as in the details of their parameterization. Taken together, functional form and parameterization, constitute what is termed a force field. Very simple force fields such as SYBYL, developed by Tripos, Inc., may easily be extended to diverse systems but would not be expected to yield quantitatively accurate results. On the other hand, a more complex force field such as MMFF94 (or more simply MMFF), developed at Merck Pharmaceuticals, while limited in scope to common organic systems and biopolymers, is better able to provide quantitative accounts of molecular geometry and conformation. Both SYBYL and MMFF are incorporated into Spartan. 

Representative examples are provided in Table 5-19. Only a single (intermolecular) distance is examined for each system, underlying the fact that the experimental structure data are incomplete. The usual quantum chemical models have been surveyed. Comparisons with molecular mechanics models have not been included even though force fields such as MMFF have been explicitly parameterized to reproduce known hydrogen-bond distances. 

Cheng et al. [166] assigned the absolute configuration of the alkaloid (—)-linarinic acid (37) with the help of theoretical calculations. Via molecular mechanics, a conformational search was performed with the MMFF force field, using water... 

CHARMM = Chemistry at Harvard Macromolecular Mechanics MMFF = Merck molecular force field QM = quantum mechanics. 

To determine the AC of the enantiomers of 3, calculations were performed in the gas phase at 298 K for the arbitrarily chosen (5)-3. As a result of the high flexibility of the prenyl chain at C2, the initial steps of conformational search and geometry optimization were carried out for a fragment molecule (Figure 53.11). Conformational search was performed at the molecular mechanics level of theory employing MM+ and MMFF force fields. The conformers with relative energy (rel E.) within 6 kcal/mol of the lowest... 

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