computer modeling in molecular biology.pdf

3 Molecular Dynamics Simulations of Peutides 43ferent conformations which are within 1-2 kcals of each other. For this reasonvarious conformational search methods have been used to attempt to explore moreof conformational space without performing a full search. Two important methodsare those based on distance geometry [lo] and those based on molecular dynamics[I 1, 121. Distance geometry techniques essentially are non-energetic techniques whichset up random distance matrices, i.e. the matrix of all distances between all atompairs in the molecule, with constraints on certain distances, e. g. bond lengths, NOEdata etc. and compute Cartesian coordinates from these matrices. Moleculardynamics is a deterministic simulation process wherein the positions and velocitiesof atoms in a molecule are integrated forward in time using Newton’s laws of motion.The initial velocities are randomly ascribed to atoms via a Maxwellian distributionconsistent with the temperature at which the simulation is being performed. Themovement of the atoms is then governed by the kinetic energy input into the systemand the restoring forces that act on the molecule when its position from a minimumenergy conformation is disturbed. The latter term is described by a forcefield fromwhich the potential energy of the system can be determined. This term consists ofstrain energies such as bond length, bond angle deformations, torsional componentsetc. and van der Waals non-bonded interactions and electrostatic terms. The ValenceForce Field (VFF) [13] AMBER [14] and CHARMM [15] are examples of forcefieldsin use to study peptide and protein conformations.3.3 Applications of Molecular DynamicsAs seen from Table 3-1, the most common use of calculations on peptides at the momentis to aid in generating conformational hypotheses in association with data fromNMR studies. Many of these studies involve NOE-restrained molecular dynamics, inwhich the experimental proton-proton distance constraints corresponding to NOEcross-relaxation rates, obtained from 2D NOESY experiments, are directly used inthe simulation [16]. Typically a harmonic term is included in the forcefield topenalise for deviations from the observed proton-proton distances.Another application is the use of relative free energy to compare chemicallydistinct systems using finite difference thermodynamic integration (FDTI) [17]. Inpractice, this is done by introducing a coupling parameter A into the forcefield whichchanges from 0 to 1 as the hamiltonians correspondingly change from state A to stateB. Results from these calculations can be directly related to experimentally obtainedthermodynamic properties.A number systems have been studied in solvent, mainly water, but some haveinvolved other solvents commonly used in NMR studies of peptides.