Stochastic conformational searching

Tel. 614-885-0657, e-mail bender(aosc.edu N. L. Allinger s molecular mechanics program for energy minimization of organic molecules. Includes CRSTL for crystal lattices, MINP for keyboard input, MEDIT for interactive editing, and VIBPLT for vibrational animation. MM2 for molecular mechanics. Stochastic conformational searching. Source code. VAX and UNIX workstations. 

In the case of small molecules a systematic or a stochastic conformational search can be applied to search the conformational space of a given molecule. 

GMMX is a stochastic conformational searching tool for small to medium-sized molecules. 

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. 

An excellent comparison of the methods employed in conformational searching of organic molecules has been published11061. In the vast majority of published inorganic molecular modeling studies no stochastic or molecular dynamics conformational searches have been conducted. There are three reasons for this. 

Random search of configurational space followed by calculation of probabilities based on a Boltzmann distribution (see energy surface, conformational search, stochastic search). 

Hence the attempt to subsume molecular mechanics under the DN-model of scientific explanation fails. It fails twice First, the stun of the force-field potentials used in molecular mechanics calculations does not have the status of a proper scientific law and the derivation of the strain energy of a molecule by molecular mechanics is not nomological. Second, the conformational search required to find stable conformations is stochastic and not deductive. 

Conformational search Scanning of a potential energy surface. Only deterministic methods (that is point-by-point searches) are fully reliable. However, these are in practice, due to the enormous computational effort, hardly ever possible. The methods currently used include random search methods (stochastic search, e.g., Monte Carlo methods) and molecular dynamics (see Potential energy surface, Deterministic search, Monte Carlo search, Stochastic search. Molecular dynamics, and Scanning an energy surface). 

Stochastic search Random search of an energy surface (see Conformational search, Deterministic search, Monte Carlo search, and Molecular dynamics). 

In principle, simulated annealing (SA) provides another methodology for ligand design. Conformational searching with SA-based methods is efficient compared with traditional molecular dynamics methods. " Further, SA can be combined with other techniques such as stochastic dynamics for greater efficiency. For example. Hart and Read combined a Monte Carlo approach with SA (described below). Also, Yue has demonstrated the ability to find bound conformations with SA. ... 

In SAR research, this directed stochastic search makes genetic algorithms a very robust and universal tool for global optimization problem of conformation search, which can be expressed in a reasonably small set of parameters. 

The various procedures that address side chain generation as an energy-driven conformational search can be grouped as systematic, combinatorial, and stochastic methods. The CONGEN procedure " includes five different tree-based implementations of the first two approaches. The first methods, named ALL, generates all possible conformations by a series of nested iterations over every side chain, and hence is limited to 7 or 8 residues. The second method, named FIRST, uses... 

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