How Good is Jarzynski’s Equality for Computer-Aided Drug Design?

Abstract

Accurate determination of the binding affinity of the ligand to the receptor remains a difficult problem in computer-aided drug design. Here, we study and compare the efficiency of Jarzynski’s equality (JE) combined with steered molecular dynamics and the linear interaction energy (LIE) method by assessing the binding affinity of 23 small compounds to six receptors, including β-lactamase, thrombin, factor Xa, HIV-1 protease (HIV), myeloid cell leukemia-1, and cyclin-dependent kinase 2 proteins. It was shown that Jarzynski’s nonequilibrium binding free energy Δ G neq Jar correlates with the available experimental data with the correlation levels R = 0.89, 0.86, 0.83, 0.80, 0.83, and 0.81 for six data sets, while for the binding free energy Δ G LIE obtained by the LIE method, we have R = 0.73, 0.80, 0.42, 0.23, 0.85, and 0.01. Therefore, JE is recommended to be used for ranking binding affinities as it provides accurate and robust results. In contrast, LIE is not as reliable as JE, and it should be used with caution, especially when it comes to new systems.

Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

“…It remains an interesting and open question whether peak forces for scaffold dislocation could be used to predict the yield of experimentally synthesized nanodiscs or whether differences in peak forces measured for different lipid loading could translate into differences in yield for syntheses having different lipid:scaffold stoichiometries or even a distribution of nanodiscs having different APL within a single experiment. If yields or distributions of nanodiscs having different lipid loading could be accurately measured, then it is possible that the combination of SMD with the Jarzinski equality could quantitatively predict these yields or distributions. − …”

Structural analysis of P450 AmphL from Streptomyces nodosus provides insights into substrate selectivity of polyene macrolide antibiotic biosynthetic P450s

“…The two main variables are the rate of movement and the force of the pull. A velocity of 10 Å/ns ( 24 ) was chosen and several pulling forces ranging from 10 to 70 kcal mol −1 Å −2 were tested ( 25 ) and, as others have found, the total energy required to push the substrate out of the active site was relatively insensitive to the choice of the pushing force ( 26 ). The minimum force that gave a smooth linear movement was 30 kcal mol −1 Å −2 .…”

Dependence of Work on the Pulling Speed in Mechanical Ligand Unbinding

“…Therefore, the use of this method is becoming more and more popular in computer-aided drug design. 9 , 11 , 13 , 15 …”

“…SMD can provide results as accurate as other standard methods for estimation of the binding free energy like MM-PBSA but computationally much faster as it deals with a non-equilibrium process related with fast pulling. Therefore, the use of this method is becoming more and more popular in computer-aided drug design. ,,, …”

“…Therefore, the use of this method is becoming more and more popular in computer-aided drug design. 9,11,13,15 It was shown 16 that non-equilibrium work, defined as…”