Calculation of the Free Energy and the Entropy of Macromolecular Systems by Computer Simulation

Stability of the Free and Bound Microstates of a Mobile Loop of α-Amylase Obtained from the Absolute Entropy and Free Energy

“…In most cases, however, one is interested in free energy differences ∆F mn , which are somewhat easier to obtain than F m and F n themselves. [13][14][15][16][17][18][19] I.3. Calculation of ∆F mn by the Counting Method and Thermodynamic Integration.…”

“…The common analysis is based on projecting MD (MC) trajectories onto a small number of coordinates using principal component analysis or calculating the populations along one or two physically significant reaction coordinates. 23,24 Differences, ∆F mn , are commonly calculated by thermodynamic integration (TI) over physical quantities such as the energy, temperature, and the specific heat 25,26 as well as nonphysical parameters [13][14][15][16][17][18][19][27][28][29][30][31][32][33][34] (free energy perturbation methods and umbrella and histogram analysis methods [35][36][37] are also included in this category, see ref 19 and references cited therein). This is a robust and highly versatile approach, which is used successfully for calculating the difference in the free energy of binding of two ligands to the active site of an enzyme.…”

Uncertainty Quantification in Alchemical Free Energy Methods

“… 4 , 8 A large number of reviews are available in the literature describing various classical molecular dynamics-based methods to calculate free energies for macromolecules. 9 − 20 There has been considerable effort put into developing new sampling protocols to accelerate phase space sampling: umbrella sampling, 21 metadynamics, 22 tempering approaches, 23 , 24 steered molecular dynamics, 25 , 26 blue moon sampling, 27 adaptive biasing force algorithm, 28 slow growth, 29 fast growth, 30 and Gaussian accelerated MD 31 to name a few. Numerous reviews are available in the literature on various approaches.…”

“…In silico free energy prediction is increasingly gaining importance given its application in drug design and personalized medicine. However, it is necessary to perform accurate, precise, and reliable free energy predictions rapidly to make actionable decisions in clinical or industrial settings. , A large number of reviews are available in the literature describing various classical molecular dynamics-based methods to calculate free energies for macromolecules. − There has been considerable effort put into developing new sampling protocols to accelerate phase space sampling: umbrella sampling, metadynamics, tempering approaches, , steered molecular dynamics, , blue moon sampling, adaptive biasing force algorithm, slow growth, fast growth, and Gaussian accelerated MD to name a few. Numerous reviews are available in the literature on various approaches. ,,− Among these, replica exchange molecular dynamics (REMD) (also known as parallel tempering) has proved to be fruitful in the case of biomolecular simulations.…”

Accurate Calculation of Conformational Free Energy Differences in Explicit Water: The Confinement–Solvation Free Energy Approach

“…For cases in which suitable reaction coordinates are not known, path-independent free energy methods offer a valuable alternative. Metadynamics and deactivated morphing are prominent examples of this family and have been successfully applied to conformational problems in explicit water. , Another approach is the hypothetical scanning method, which has been applied to peptide chains immersed in a box of explicit water . Within this family, the confinement method, , which is related to Einstein’s early work on crystals and later developments, , aims at the free energy of conformation by restraining the actual conformational ensembles to the harmonic state of reference, whose free energy is known analytically.…”