LARGE SCALE MOLECULAR STRUCTURE INVESTIGATION OF FLEXIBLE MOLECULES AND WEB-PORTAL CREATION FOR CONFORMATION RETRIEVAL

Abstract

Triglycerides are involved in important biological functions. Their numerous stable conformations radically influence their properties. We intend to exhaustively investigate the stable conformations of certain short chain triglycerides using well established Molecular Mechanics force fields and sophisticated global optimization techniques. The large amount of results will be handled by a database publicly accessible through a Web-portal. Subsequent refinement with Quantum Mechanical ab-initio calculations will also be offered via the portal.

 

Detailed description

The importance of triglycerides (fats) in the biological cycle can hardly be overestimated [1]. They serve as structural components of cell membranes and as a source of carbon atoms for biosynthetic reactions. Body fats are the most important energy reserve in animals and in addition are excellent thermal and electrical insulators. Among other things they serve as mechanical padding in the subcutaneous tissue and around organs. Triglycerides are also important raw materials in the food industry.

Triglycerides are highly flexible molecules thus adopting a large number of structural arrangements (conformations). In a recent study of triacetin [2], 109 different conformers were discovered, within an energy range of 3 Kcal/mol from the global minimum. The number of conformers grows rapidly with the carbon chain length.

We intend to exhaustively investigate the following triglycerides:

An estimate of the anticipated number of conformers for the above triglycerides along with the required single-cpu time on a 400MHz Sun450 is presented in the following table. Clearly more processing power enables the solution of larger sized problems.

Triglyceride

Number of conformers

Estimated CPU time

Triacetin

1000

15 min

Tripropionin

25000

20 hours

Tributyrin

700000

40 days

Trivalerin

18900000

60 months

We employ the Molecular Mechanics approach [3] using the well established MM2 [4], MM3 [5] (and perhaps CHARMM [6], AMBER [7]) all-atom force fields with appropriate parameters, as implemented by the Tinker [8] molecular modeling package. For a given molecule, the objective is to find the conformation corresponding to the global minimum of the steric energy functional, along with all the conformations corresponding to local minima within a prescribed energy range above the global value.

For the local minimization the Merlin Optimization Environment [9] will be used. This software package has been developed by our research team and the most recent version (3.0) appeared in the literature in 1998. Merlin offers a command driven, friendly user interface and robust implementations of state-of-the-art optimization algorithms. In addition the Merlin Control Language (MCL) [10], has been developed thus enabling the creation of optimization strategies. The global optimization algorithms will be written in MCL. This approach has been successfully applied with earlier versions of the above software packages and our results can be found in [2].

We propose to implement Stochastic [11] (Multistart, Simulated Annealing, Clustering) and Genetic algorithms [12] for global optimization with local tuning. Neural Network classification techniques will be used to accelerate the process by timely abandoning uninteresting points. These stochastic Global Optimization techniques lend themselves to parallel and/or distributed processing. Hence the load of the local optimization tasks will be distributed across a number of processors.

The resulting conformations will be stored in a database (MySQL [13]) in order to ease their handling, retrieval and further employment (visualization, ab-initio calculations).

In order to make our results available to the public we intend to create a web-portal. Through the portal one will be able to retrieve and visualize any of the stored conformations. In addition the portal will accept orders for further refining ab-initio calculations on any of the stored conformers using the GAMESS [14] package. A separate database will keep track of these quantum mechanical results.

 

References

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