K Vengadesan | PubMed Health

PubMed2004

Conformational studies on enkephalins using the MOLS technique.

Conformational studies of two linear enkephalin molecules, Met-enkephalin and Leu-enkephalin, have been carried using the mutually orthogonal Latin squares (MOLS) technique with the ECEPP/3 force field. This technique was developed recently in our laboratory to perform an unbiased search of the conformational space of peptides and to locate low energy conformations. The present study identified all the folds predicted by other studies, and in addition picked up other energetically favorable structures. The results suggest that the peptide backbone exists as a mixture of folded and unfolded forms (approximately 50% each). The study also provides information on the distribution of the low energy conformations that we have classified on the basis of structural motifs, backbone hydrogen-bonding patterns, and root mean square deviations in atomic positions.

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PubMed2004

An application of experimental design using mutually orthogonal Latin squares in conformational studies of peptides.

We address the question-can we use experimental design methods to investigate peptide conformation and identify conformational parameters that may contribute more significantly to the potential energy than others? We used mutually orthogonal Latin square design to sample the conformational space of peptides and analysed the samples using analysis of variance. We examined the equality of the effect of the torsion angles on the conformational potential energy. The results showed that different torsion angles contributed differently to the conformational energy. We are able to identify those parameters that may have to be more carefully considered in conformational studies of peptides.

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PubMed2003

Enhanced sampling of the molecular potential energy surface using mutually orthogonal latin squares: application to peptide structures.

The computational identification of the optimal three-dimensional fold of even a small peptide chain from its sequence, without reference to other known structures, is a complex problem. There have been several attempts at solving this by sampling the potential energy surface of the molecule in a systematic manner. Here we present a new method to carry out the sampling, and to identify low energy conformers of the molecule. The method uses mutually orthogonal Latin squares to select (of the order of) n(2) points from the multidimensional conformation space of size m(n), where n is the number of dimensions (i.e., the number of conformational variables), and m specifies the fineness of the search grid. The sampling is accomplished by first calculating the value of the potential energy function at each one of the selected points. This is followed by analysis of these values of the potential energy to obtain the optimal value for each of the n-variables separately. We show that the set of the n-optimal values obtained in this manner specifies a low energy conformation of the molecule. Repeated application of the method identifies other low energy structures. The computational complexity of this algorithm scales as the fourth power of the size of the molecule. We applied this method to several small peptides, such as the neuropeptide enkephalin, and could identify a set of low energy conformations for each. Many of the structures identified by this method have also been previously identified and characterized by experiment and theory. We also compared the best structures obtained for the tripeptide (Ala)(3) by the present method, with those obtained by an exhaustive grid search, and showed that the algorithm is successful in identifying all the low energy conformers of this molecule.

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