![]() In this short perspective we remark that the long sought calculation of free energies from end point simulations may be afforded with reasonable accuracy from implicit solvent end-point simulations. ![]() The problem with the computation of the entropy from a single MD simulation is that only part of the configurational space is accessed by simulation. ![]() If the two end-points are close enough a simulation of one or both end-points may be performed and free energy differences obtained by free energy perturbation ( Zwanzig, 1954), but this is not possible in general. In molecular simulations typically only near-equilibrium configurations are sampled.įor this reason free energy differences calculation is performed using methods, like umbrella sampling ( Torrie and Valleau, 1977), thermodynamic integration ( Straatsma and McCammon, 1991) or metadynamics ( Laio and Parrinello, 2002), that compute by various methods the free energy along a pathway connecting end-point states, even if it is often just the difference in free energy between the latter points that is actually needed. However, as pointed out many years ago ( Beveridge and DiCapua, 1989), this formula is of no practical use unless all configurational space enters (implicitly or explicitly) the average, because lowest probability configurations display the highest value contribution to the average and there cannot be convergence for upper unbound potentials. Where R is the gas constant, T the temperature, β is equal to 1 R T, U is the potential energy and ⟨⟩ indicates thermodynamic ensemble average. We review briefly the basic theory and discuss the advancements in light of practical applications. More recently outstanding advancement in both implicit solvent models and in entropy calculations are making the goal of free energy estimation from end-point simulations more feasible than ever before. In the last two decades implicit solvent models have been used to circumvent the problem and to take into account solvent entropy implicitly in the solvation terms. Since the enthalpy may be calculated as the ensemble average over equilibrated simulation snapshots the difficulties related to free energy calculation are ultimately related to the calculation of the entropy of the system and in particular of the solvent entropy. In this perspective we consider the calculation of free energy, enthalpy and entropy from end-point molecular dynamics simulations. 4Science and Math Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emiratesįree energy is the key quantity to describe the thermodynamics of biological systems. ![]() 3Dipartimento di Area Medica, Universita' di Udine, Udine, Italy.2Istituto Nazionale Biostrutture e Biosistemi, Rome, Italy.1Dipartimento di Scienze Matematiche, Informatiche e Fisiche, Universita' di Udine, Udine, Italy.Federico Fogolari 1,2 * Alessandra Corazza 2,3 Gennaro Esposito 1,2,4 ![]()
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