Molecular conformation conformational search

It may be desirable to predict which crystal structure is most stable in order to predict the products formed under thermodynamic conditions. This is a very difficult task. As of yet, no completely automated way to try all possible crystal structures formed from a particular collection of elements (analogous to a molecular conformation search) has been devised. Even if such an effort were attempted, the amount of computer power necessary would be enormous. Such studies usually test a collection of likely structures, which is by no means infal-... 

Saunders 26 introduced a method that performs random molecular conformational searches in Cartesian rather than internal space. In this method, one starts with an initial conformation. Every atom in the molecule is given a... 

Figure 4.49 reprinted with permission from Pranata J and W L Jorgensen. Computational Studies on FK506 Conformational Search and Molecular Dynamics Simulations in Water. The Journal of the American Chemical Society 113 9483-9493. 1991 American Chemical Society. 

The input to a minimisation program consists of a set of initial coordinates for the system. The initial coordinates may come from a variety of sources. They may be obtained from an experimental technique, such as X-ray crystallography or NMR. In other cases a theoretical method is employed, such as a conformational search algorithm. A combination of experimenfal and theoretical approaches may also be used. For example, to study the behaviour of a protein in water one may take an X-ray structure of the protein and immerse it in a solvent bath, where the coordinates of the solvent molecules have been obtained from a Monte Carlo or molecular dynamics simulation. 

Since computation time is the most important bottleneck to conformation searching, the following list starts with the methods most amenable to the largest molecular systems ... 

Another technique employs a database search. The calculation starts with a molecular structure and searches a database of known spectra to find those with the most similar molecular structure. The known spectra are then used to derive parameters for inclusion in a group additivity calculation. This can be a fairly sophisticated technique incorporating weight factors to account for how closely the known molecule conforms to typical values for the component functional groups. The use of a large database of compounds can make this a very accurate technique. It also ensures that liquid, rather than gas-phase, spectra are being predicted. 

The molecular mechanics force fields available include MM+, OPLS, BIO+, and AMBER. Parameters missing from the force field will be automatically estimated. The user has some control over cutoff distances for various terms in the energy expression. Solvent molecules can be included along with periodic boundary conditions. The molecular mechanics calculations tested ran without difficulties. Biomolecule computational abilities are aided by functions for superimposing molecules, conformation searching, and QSAR descriptor calculation. 

PC Model has some features that are not found in many other molecular mechanics programs. This is one of the few programs that outputs the energy given by the force field and the heat of formation and a strain energy. Atom types for describing transition structures in the MMX force field are included. There is a metal coordination option for setting up calculations with metal atoms. There are also molecular similarity and conformation search functions. 

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. 

One of the most important considerations in using molecular dynamics for a conformational search is determining the sampling interval. HyperChem lets you sample the simulation in two ways ... 

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. 

The choice of heating time depends on the purpose of the molecular dynamics simulation. If the simulation is for conformational searches, the heating step is not critical for a successful calculation. The heating step may be rapid to induce large structural changes that provide access to more of the conformational space. 

At present, conformational searches provide for the most important application of computer molecular modeling in biology. In contrast, in statistical physics, from which MC and MD methods were originally borrowed, they are primarily used for studying... 

To overcome the limitations of the database search methods, conformational search methods were developed [95,96,109]. There are many such methods, exploiting different protein representations, objective function tenns, and optimization or enumeration algorithms. The search algorithms include the minimum perturbation method [97], molecular dynamics simulations [92,110,111], genetic algorithms [112], Monte Carlo and simulated annealing [113,114], multiple copy simultaneous search [115-117], self-consistent field optimization [118], and an enumeration based on the graph theory [119]. 

Lipton, M Still, W. C. The multiple minimum problem in molecular modeling. Tree searching internal coordinate conformational space. J. Comp. Chem. 1988, 9, 343-355. 

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