Free Energy Simulation Method Research Articles

Simulation analysis of the stability mutant R96H of T4 lysozyme

Free energy simulation methods are used to analyze the effects of the mutation Arg 96----His on the stability of T4 lysozyme. The calculated stability change and the lack of significant structural rearrangement in the folded state due to the mutation are in agreement with experimental studies [Kitamura, S., & Sturtevant, J. M. (1989) Biochemistry 28, 3788-3792; Weaver, L. H., et al. (1989) Biochemistry 28, 3793-3797]. By use of thermodynamic integration, the contributions of specific interactions to the free energy change are evaluated. It is shown that a number of contributions that stabilize the wild type or the mutant partially cancel in the overall free energy difference; some of these involve the unfolded state. Comparison of the results with conclusions based on structural and thermodynamic data leads to new insights into the origin of the stability difference between wild-type and mutant proteins. Of particular interest is the importance of the contributions of more distant residues, solvent water, and the covalent linkage of the mutated amino acid. Also, the analysis of the interactions of Arg/His 96 with the C-terminal end of a helix (residues 82-90) makes it clear that the nearby carbonyl groups (Tyr 88 and Asp 89) make the dominant contribution, that the amide groups do not contribute significantly, and that the helix-dipole model is inappropriate for this case.

Free Energy Simulation of Grain Boundary Segregation and Thermodynamics In Ni3−xAl1+x

ABSTRACTThe free energy simulation method is employed to study segregation to Σ5 and Σ13 (001) twist grain boundaries and their free energies in ordered Ni3−xAl1+x. In the temperature range studied (300–900K), it is shown that there is almost no segregation, strong Al segregation, and weak Ni segregation to the grain boundary for the stoichiometric, Al-rich, and Ni-rich bulk compositions respectively. It is also shown that the segregation is limited to a few (002) planes around the grain boundary and its magnitude decreases with increasing temperature. For Al-rich bulk composition, it is demonstrated that segregation at low temperature substantially lowers the grain boundary free energy.

Protein–drug interactions: Characterization of inhibitor binding in complexes of DHFR with trimethoprim and related derivatives

Structural and thermodynamic interactions for the binding of trimethoprim and related congeners to the binary complex of dihydrofolate reductase (from chicken) and NADPH are explored using free energy simulation methods. Good agreement between structures from experimental X-ray refinement and molecular dynamics simulations is found for the complexes. Agreement with thermodynamic measurements is found as well. Our thermodynamic calculations suggest that entropic contributions and desolvation thermodynamics can play a crucial role in overall binding, and that extreme care must be taken in the use of simple model building to rationalize or predict protein-drug binding.

Thermodynamic calculations on biological molecules

Application of free-energy simulation methods to the calculation of thermodynamic properties for biologically relevant processes will be presented. Attention will be given to the usefulness of thermodynamic methods to explore the accuracy of empirical energy functions. Calculations of aqueous hydration and binding thermodynamics for drug molecules (trimethoprim and other related compounds) to biological targets (the enzyme dihydrofolate reductase) will be presented. In these applications we will discuss differences in “binding modes” for different drugs and the ability of thermodynamic methods to predict these changes. Finally, comments will be made regarding the free energy derivative methods and coordinate-coupled free energy calculations.