Conformational search techniques

Side chain generation is often a source of error. It will be most reliable if certain rules of thumb are obeyed. Start with structurally conserved side chains and hold them fixed. Then look at the energy and entropy of rotamers for the remaining side chains. Conventional conformation search techniques are often used to place each side chain. 

Use conventional conformation search techniques to optimize side chains. 

Conformation search techniques can be used to find very-low-energy conformations, which are most relevant to polymers that will be given a long annealing time. 

Most drug-like molecules adopt a number of conformations through rotations about bonds and/or inversions about atomic centers, giving the molecules a number of different three-dimensional (3D) shapes. To obtain different energy minimized structures using a force field, a conformational search technique must be combined with the local geometry optimization described in the previous section. Many such methods have been formulated, and they can be broadly classified as either systematic or stochastic algorithms. 

The multiple-minimum problem is a severe handicap of many large-scale optimization applications. The state of the art today is such that for reasonable small problems (30 variables or less) suitable algorithms exist for finding all local minima for linear and nonlinear functions. For larger problems, however, many trials are generally required to find local minima, and finding the global minimum cannot be ensured. These features have prompted research in conformational-search techniques independent of, or in combination with, minimization.26... 

Recently, it was hypothesized that native protein structure is specified by a stereochemical code (1). We have been evaluating this hypothesis by examining high resolution protein structures to extract recurrent patterns and identify formative interactions (2,3). Many patterns are smeill enough to be analyzed exhaustively by conformational search techniques. 

MOE assigns a value of 1 or -1 for chiral molecules and zero for achiral molecules. DAPPER, was developed with this in mind and therefore can easily incorporate different conformation search techniques and chirahty metrics. A new chirality measure provides a quantitative description of the overaU chirahty of a given conformation of a molecule without assigning values to individual atoms. In this article, they discuss the analysis of several implementations of various conformation search techniques, a novel chirahty metric, and their incorporation into DAPPER with validation on three standard medicinal chemistry data sets (dihydrofolate reductase, angiotensin converting enzyme, acetylchohn-esterase). They have demonstrated clear predictive power in the case of 20 DHFR inhibitors [48]. 

The major aim of conformational analysis is to identify the preferred conformations of a molecule under specific conditions. Therefore, conformational search techniques (i.e., methods that locate the global and local energy minima of a structure) play a crucial role in conformational analysis. 

Figure 4 General work flow of conformational search techniques.

Geometry optimization of the proposed mimetic is included as part of the design analysis to ensure the feasibility of the desired molecular conformation. MM and semiempirical quantum mechanical methods have been used most extensively for these purposes. Conformational analysis of the proposed mimetic allows the determination of an energy profile for the molecule under consideration. This has been used by researchers to assess where the desired conformation for the mimetic resides on the molecular potential energy surface. Monte Carlo, MD, and distance geometry-based conformational search techniques have been employed extensively to sample conformational space. Computational methods that attempt to approximate the efifects of aqueous solvation on the conformational profile of the mimetic are being used more frequently as part of these efforts. 

Vengadesan K, Gautham N (2005) A new conformational search technique and its applications. Curr Sci India 88 1759-1770... 

The initial guess for the iterative minimization process can be derived from experimental data, where available, or from results of conformational search techniques. 

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