ABSTRACT:The Dynamo module library has been developed for the simulation of molecular systems using hybrid quantum mechanical (QM) and molecular mechanical (MM) potentials. Dynamo is not a program package but is a library of Fortran 90 modules that can be employed by those interested in writing their own programs for performing molecular simulations. The library supports a range of different types of molecular calculation including geometry optimizations, reaction-path determinations and molecular dynamics and Monte Carlo simulations. This article outlines the general structure and capabilities of the library and describes in detail Dynamo's semiempirical QM/MM hybrid potential. Results are presented to indicate three particular aspects of this implementation-the handling of long-range nonbonding interactions, the nature of the boundary between the quantum mechanical and molecular mechanical atoms and how to perform path-integral hybrid-potential molecular dynamics simulations.

The neuraminidase from the influenza virus is essential for maintaining viral infectivity as it aids in the transmission of the virus between cells. Although there are large variations in the amino acid sequences of neuraminidases from different influenza strains, there are several amino acids in the active site region of the protein that are strictly conserved. This has raised hopes that a single neuraminidase inhibitor and, hence a drug, can be found that is effective against all influenza strains. In this paper, we examine with theoretical simulation techniques one aspect of the reaction catalyzed by the viral neuraminidase that could be important for inhibitor design studiesnamely, whether a covalently bound complex can be formed between the enzyme and the sialosyl cation intermediate that occurs during the reaction. We used a hybrid semiempirical quantum mechanical/molecular mechanical (QM/MM) potential in conjunction with potential of mean force calculations to determine the free-energy profiles for formation of the covalent intermediate and its hydrolysis to sialic acid and for the direct hydroxylation of the sialosyl cation to sialic acid. Ab initio QM calculations were used to check the validity of the semiempirical results. We find that direct hydroxylation of the sialosyl cation is the energetically preferred pathway but not by so much that the possibility of being able to design covalently bound inhibitors need be completely abandoned.

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