| Summary: | In the context of computational drug design, we examine the effectiveness of the enhanced sampling techniques in state-of-the-art free energy calculations based on alchemical molecular dynamics simulations. In a paradigmatic molecule with competition between conformationally restrained E and Z isomers whose probability ratio is strongly affected by the coupling with the environment, we compare the so-called <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-hopping technique to the Hamiltonian replica exchange methods assessing their convergence behavior as a function of the enhanced sampling protocols (number of replicas, scaling factors, simulation times). We found that the pure <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-hopping, commonly used in solvation and binding free energy calculations via alchemical free energy perturbation techniques, is ineffective in enhancing the sampling of the isomeric states, exhibiting a pathological dependence on the initial conditions. Correct sampling can be restored in <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-hopping simulation by the addition of a “hot-zone” scaling factor to the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>λ</mi></semantics></math></inline-formula>-stratification (FEP<sup>+</sup> approach), provided that the additive hot-zone scaling factors are tuned and optimized using preliminary ordinary replica-exchange simulation of the end-states.
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