Molecular mechanics local minimum

Once the model of a ligand-receptor complex is built, its stability should be evaluated. Simple molecular mechanics optimization of the putative ligand-receptor complex leads only to the identification of the closest local minimum. However, molecular mechanics optimization of molecules lacks two crucial properties of real molecular systems temperature and, consequently, motion. Molecular dynamics studies the time-dependent evolution of coordinates of complex multimolecular systems as a function of inter- and intramolecular interactions (see Chapter 3). Because simulations are usually performed at nonnal temperature (—300 K), relatively low energy barriers, on the order of kT (0.6 kcal), can... 

Molecular mechanics calculations on dendrimer 28 and 15 reveal the existence of several local minima. To obtain the global energy minimum, one-half of... 

There are two outcomes of a single molecular mechanics calculation the structural geometry of a local eneigy minimum, or the global energy minimum, and the energy value of that minimum. The way these data can be used will be considered separately. 

Molecular mechanics (MM) and dynamics (MD) are useful tools to investigate the conformational properties of organic molecules. (75) In particular, the combined use of MM and MD can be very effective in sampling the potential energy hypersurface (PES) when structurally constrained molecules are considered. In the present work, the PES has been described using the MM+ forcefield (16) and MM optimizations were followed by short MD runs (10 ps) carried out at different temperature (from 300 to 700 K) in order to sample the PES efficiently. Usually, due to the steric properties of the molecules investigated, no more than 10 MM/MD cycles were necessary to localize all the relevant energy minimum structures. 

In molecular quantum mechanics, the analytical calculation of G is very time consuming. Furthermore, as discussed later, the Hessian should be positive definite to ensure a step in the direction of the local minimum. One solution to this later problem is to precondition the Hessian matrix and this is discussed for the restricted step methods. The Quasi-Newton methods, presented next, provides alternative solution to both of these problems. 

When nuclei in molecules are treated classically, the concept of molecular geometry emerges in a natural way. To be more precise, the equilibrium geometry is defined as the set of internal coordinates r for which the ground-state eigenvalue q(r) of the electronic Hamiltonian attains a local minimum. Different minima in q(r) correspond to equilibrium geometries of isomeric species with identical compositions. Needless to say, this naive picture is inevitably lost in a fully quanturn-mechanical treatment. 

The molecular mechanics routine is highly interactive and relies on graphical input and output. A molecule being modelled can be displayed in any desired orientation for inspection by the user. If such inspection shows that the model is trapped in a local minimum of the strain energy, then interactive routines allow the user to alter the model to bring it out of the minimum. 

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