Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T0) and liganded (R4) tetramers are stable in solution, the published MD simulations of T0 undergo a rapid quaternary transition to an R-like structure. We show that T0 is stable only when the periodic solvent box contains ten times more water molecules than the standard size for such simulations. The results suggest that such a large box is required for the hydrophobic effect, which stabilizes the T0 tetramer, to be manifested. Even in the largest box, T0 is not stable unless His146 is protonated, providing an atomistic validation of the Perutz model. The possibility that extra large boxes are required to obtain meaningful results will have to be considered in evaluating existing and future simulations of a wide range of systems.
The coronavirus SARS-CoV-2 main protease, M
pro
, is conserved among
coronaviruses with no human homolog and has therefore attracted significant attention as
an enzyme drug target for COVID-19. The number of studies targeting M
pro
for
in silico screening has grown rapidly, and it would be of great interest to know in
advance how well docking methods can reproduce the correct ligand binding modes and rank
these correctly. Clearly, current attempts at designing drugs targeting M
pro
with the aid of computational docking would benefit from a priori knowledge of the
ability of docking programs to predict correct binding modes and score these correctly.
In the current work, we tested the ability of several leading docking programs, namely,
Glide, DOCK, AutoDock, AutoDock Vina, FRED, and EnzyDock, to correctly identify and
score the binding mode of M
pro
ligands in 193 crystal structures. None of the
codes were able to correctly identify the crystal structure binding mode (lowest energy
pose with root-mean-square deviation < 2 Å) in more than 26% of the cases for
noncovalently bound ligands (Glide: top performer), whereas for covalently bound ligands
the top score was 45% (EnzyDock). These results suggest that one should perform in
silico campaigns of M
pro
with care and that more comprehensive strategies
including ligand free energy perturbation might be necessary in conjunction with virtual
screening and docking.
Despite considerable effort, a molecular-level understanding of the mechanisms governing adsorption/desorption in reversed-phase liquid chromatography is still lacking. This impedes rational design of columns and the development of reliable, computationally more efficient approaches to predict the selectivity of a particular column design. Using state-of-the art, validated force fields and free-energy simulations, the adsorption thermodynamics of benzene derivatives is investigated in atomistic detail and provides a quantitative microscopic understanding of retention when compared with experimental data. It is found that pure partitioning or pure adsorption is rather the exception than the rule. Typically, a pronounced ∼1 kcal/mol stabilization on the surface is accompanied by a broad trough indicative of partitioning before the probe molecule incorporates into the mobile phase. The present findings provide a quantitative and rational basis to develop improved effective, coarse-grained computational models and to design columns for specific applications.
Fully atomistic simulations of water/methanol mixtures of varying compositions (80/20 and 50/50) at chromatographic interfaces with different functionalizations are presented. The dynamical properties in terms of equilibration times and solvent exchange dynamics are characterized and found to depend on the different systems on the nanosecond time scale. The solvent density profile and the structuring of the stationary phase differ for derivatizations including (-CN, NO(2), -NH(2), -C(6)H(5)) of the C(18) chain. The time scale and intensity of the water exchange dynamics differs for the different realizations of the chromatographic systems and ranges from 200 to 500 ps. Water exchange rates depend on solvent composition as well as on the functionalization of alkyl chains. Simulations with acridine as a probe molecule provide atomistic insight into the slot model.
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