Conformation search Molecular geometry

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... 

For a conformation in a relatively deep local minimum, a room temperature molecular dynamics simulation may not overcome the barrier and search other regions of conformational space in reasonable computing time. To overcome barriers, many conformational searches use elevated temperatures (600-1200 K) at constant energy. To search conformational space adequately, run simulations of 0.5-1.0 ps each at high temperature and save the molecular structures after each simulation. Alternatively, take a snapshot of a simulation at about one picosecond intervals to store the structure. Run a geometry optimization on each structure and compare structures to determine unique low-energy conformations. 

You can often use experimental data, such as Nuclear Overhauser Effect (NOE) signals from 2D NMR studies, as restraints. NOE signals give distances between pairs of hydrogens in a molecule. Use these distances to limit distances during a molecular mechanics geometry optimization or molecular dynamics calculation. Information on dihedral angles, deduced from NMR, can also limit a conformational search. 

A molecular dynamics simulation used for a conformational search can provide a quick assessment of low energy conformers suitable for further analysis. Plot the average potential energy of the molecule at each geometry. This plot may also suggest conformational changes in a molecule. 

Molecular mechanics models are restricted to the description of molecular equilibrium geometry and conformation. They are the method of choice for conformational searching on complex systems. 

These workers proceeded to carry out theoretical conformational analyses of a set of sweeteners, many of which have multiple A-H and/or B sites. The set of compounds analyzed are reported in Table I along with the sweet potency relative to sucrose. A fixed valence geometry molecular mechanics force field was used in the conformational analyses. The conformational search strategy was as follows ... 

Metalloenzymes pose a particular problem to both experimentalists and modelers. Crystal structures of metalloenzymes typically reveal only one state of the active site and the state obtained frequently depends on the crystallization conditions. In some cases, states probably not relevant to any aspect of the mechanism have been obtained, and in many cases it may not be possible to obtain states of interest, simply because they are too reactive. This is where molecular modeling can make a unique contribution and a recent study of urease provides a good example of what can be achieved119 1. A molecular mechanics study of urease as crystallized revealed that a water molecule was probably missing from the refined crystal structure. A conformational search of the active site geometry with the natural substrate, urea, bound led to the determination of a consensus binding model[I91]. Clearly, the urea complex cannot be crystallized because of the rate at which the urea is broken down to ammonia and, therefore, modeling approaches such as this represent a real contribution to the study of metalloenzymes. 

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