Energy Simulations

Boresch, S., Archontis, G., Karplus, M. Free energy simulations The meaning of the individual contributions from component analysis. Proteins Str. Funct. Genet., 20 (1994) 25-33... 

Hermans, J. A simple analysis of noise and hysteresis in free energy simulations. J. Phys. Chem. 95 (1991) 9029-9032... 

Conformational free energy simulations are being widely used in modeling of complex molecular systems [1]. Recent examples of applications include study of torsions in n-butane [2] and peptide sidechains [3, 4], as well as aggregation of methane [5] and a helix bundle protein in water [6]. Calculating free energy differences between molecular states is valuable because they are observable thermodynamic quantities, related to equilibrium constants and... 

Table 3. Conformational free energy simulation of linear DPDPE. Changes in free energy and its components. Units kcal/mol...

K. Kuczera. One- and multidimensional conformational free energy simulations. J. Comp. Chem., 17 1726-1749, 1996. 

For constant energy simulations without temperature regulation, use heating steps of about 0.5 ps and a healing time of 20-30 ps. In gen eral, short h eating tim es and large temperature steps perturb th e initial system m ore than Ion gcr heating times and small tern -perature steps. 

Mezei M and D L Beveridge 1986. Free Energy Simulations. In Beveridge D L and W L Jorgens (Editors) Computer Simulation of Chemical and Biomolecular Systems. Annals of the New Y Academy of Sciences 482 1-23. 

Boresch S, G Archontis and M Karplus 1994. Free Energy Simulations The Meaning of the Indi-. id Contributions from a Component. Analysis. Proteins Structure, Function and Gau tics 20 25-33. 

Sir Isaac Newton spent much of his life pursuing an elusive dream, the transmutation of base materials into gold. Though he was not successful during his lifetime, he did manage to discover the equations of motion that, tliree centuries later, make alchemy possible on a computer. To perfonn this feat, Newton s equations need only be supplemented by the modem technology of free energy simulations. 

Another variant that may mrn out to be the method of choice performs the alchemical free energy simulation with a spherical model surrounded by continuum solvent, neglecting portions of the macromolecule that lie outside the spherical region. The reaction field due to the outer continuum is easily included, because the model is spherical. Additional steps are used to change the dielectric constant of that portion of the macromolecule that lies in the outer region from its usual low value to the bulk solvent value (before the alchemical simulation) and back to its usual low value (after the alchemical simulation) the free energy for these steps can be obtained from continuum electrostatics [58]. 

Finally, an alchemical free energy simulation is needed to obtain the free energy difference between any one substate of system A and any one substate of system B, e.g., Ai- In practice, one chooses two substates that resemble each other as much as possible. In the alchemical simulation, it is necessary to restrain appropriate parts of the system to remain in the chosen substate. Thus, for the present hybrid Asp/Asn molecule, the Asp side chain should be confined to the Asp substate I and the Asn side chain confined to its substate I. Flat-bottomed dihedral restraints can achieve this very conveniently [38], in such a way that the most populated configurations (near the energy minimum) are hardly perturbed by the restraints. Note that if the substates AI and BI differ substantially, the transfomnation will be difficult to perform with a single-topology approach. 

A powerful and general technique to enhance sampling is the use of umbrella potentials, discussed in Section IV. In the context of alchemical free energy simulations, for example, umbrella potentials have been used both to bias the system toward an experimentally determined conformation [26] and to promote conformational transitions by reducing dihedral and van der Waals energy terms involving atoms near a mutation site [67]. 

A Tropsha, J Hermans. Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HIV protease. Protein Eng 51 29-34, 1992. 

The free energy changes of the outer shell upon reduction, AG° , are important, because the Nernst equation relates the redox potential to AG. Eree energy simulation methods are discussed in Chapter 9. Here, the free energy change of interest is for the reaction... 

Free energy simulations are a useful means of quantitating whether the free energy and not simply the energy is shifting in the predicted manner for the mutant (see Chapter 9). The difference in the free energy changes upon reduction between a wild-type and a mutant, AAG = AG — AG, where the asterisk indicates the mutant, can be calculated in two ways via the thennodynamic cycle shown in Scheme 2,... 

Clarke J. A. Energy simulation in building design. Bristol and Boston Adam Flilget, 1985. 

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