Amyloid beta (Aβ) oligomers are neurotoxic compounds that destroy the brain of Alzheimer's disease patients. Recent studies indicated that the trimer is one of the most cytotoxic forms of low molecular weight Aβ oligomers. As there was limited information about the structure of the Aβ trimer, either by experiment or by computation, we determined in this work the structure of the 3Aβ oligomer for the first time using the temperature replica exchange molecular dynamics simulations in the presence of an explicit solvent. More than 20.0 μs of MD simulations were performed. The probability of the β-content and random coil structure of the solvated trimer amounts to 42 ± 6 and 49 ± 7% which is in good agreement with experiments. Intermolecular interactions in central hydrophobic cores play a key role in stabilizing the oligomer. Intermolecular polar contacts between D23 and residues 24-29 replace the salt bridge D23-K28 to secure the loop region. The hydrophilic region of the N-terminus is maintained by the intermolecular polar crossing contacts H13A-Q15B and H13B-Q15C. The difference in the free energy of binding between the constituting monomers and the others amounts to -36 ± 8 kcal mol. The collision cross section of the representative structures of the trimer was computed to be 1330 ± 47 Å, which is in good agreement with previous experiments.

Binding affinity of a small ligand to a receptor is the important quantity in drug design, and it might be characterized by different quantities. The most popular one is the binding free energy, which can be estimated by several methods in conventional molecular dynamics simulation. So far in steered molecular dynamics (SMD), one can use either the rupture force or nonequilibrium pulling work as a measure for binding affinity. In this paper, we have shown that the nonequilibrium binding free energy Δ G, obtained by Jarzynski's equality at a finite pulling speed, has good correlation with experimental data on inhibition constants, implying that this quantity can be used as a good scoring function for binding affinity. A similar correlation has also been disclosed for binding and unbinding free energy barriers. Applying the SMD method to unbinding of 23 small compounds from the binding site of β-lactamase protein, a bacteria-produced enzyme, we have demonstrated that the rupture or unbinding time strongly correlates with experimental data with correlation level R ≈ 0.84. As follows from the Jarzynski's equality, the rupture time depends on the unbinding barrier exponentially. We show that Δ G, the rupture time, and binding and unbinding free energy barriers are good descriptors for binding affinity. Our observation may be useful for fast screening of potential leads as the SMD simulation is not time-consuming. On the basis of nonequilibrium simulation, we disclosed that, in agreement with the experiment, the binding time is much longer than the unbinding one.

The outbreak of a new coronavirus SARS-CoV-2 (severe acute respiratory syndrome–coronavirus 2) has caused a global COVID-19 (coronavirus disease 2019) pandemic, resulting in millions of infections and thousands of deaths around the world. There is currently no drug or vaccine for COVID-19, but it has been revealed that some commercially available drugs are promising, at least for treating symptoms. Among them, remdesivir, which can block the activity of RNA-dependent RNA polymerase (RdRp) in old SARS-CoV and MERS-CoV viruses, has been prescribed to COVID-19 patients in many countries. A recent experiment showed that remdesivir binds to SARS-CoV-2 with an inhibition constant of μM, but the exact target has not been reported. In this work, combining molecular docking, steered molecular dynamics, and umbrella sampling, we examined its binding affinity to two targets including the main protease (Mpro), also known as 3C-like protease, and RdRp. We showed that remdesivir binds to Mpro slightly weaker than to RdRp, and the corresponding inhibition constants, consistent with the experiment, fall to the μM range. The binding mechanisms of remdesivir to two targets differ in that the electrostatic interaction is the main force in stabilizing the RdRp–remdesivir complex, while the van der Waals interaction dominates in the Mpro–remdesivir case. Our result indicates that remdesivir can target not only RdRp but also Mpro, which can be invoked to explain why this drug is effective in treating COVID-19. We have identified residues of the target protein that make the most important contribution to binding affinity, and this information is useful for drug development for this disease.

No 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.

The outbreak of a new coronavirus SARS-CoV-2 (severe acute respiratory syndrome–<br>coronavirus 2) has caused a global CoVid-19 (coronavirus disease 2019) pandemic, resulting in millions of infections and thousands of deaths around the world. There is currently no drug or vaccine for CoVid-19, but it has been revealed that some commercially available drugs are promising, at least for treating symptoms. Among them, Remdesivir, which can block the activity of RNA-dependent RNA polymerase (RdRp) in old SARS-CoV and MERS-CoV viruses, has been prescribed to CoVid-19 patients in many countries. A recent experiment showed that Remdesivir binds to SARS-CoV-2 with an inhibition constant of μM, but the exact target has not been reported. In this work, combining molecular docking, steered molecular dynamics and umbrella sampling we examined its binding affinity to two targets including the main protease (Mpro), also known as 3C-like protease, and RdRp. We showed that Remdesivir binds to Mpro slightly weaker than to RdRp and the corresponding inhibition constants, consistent with the experiment, fall to the μM range. The binding mechanisms of<br>Remdesivir to two targets differ in that electrostatic interaction is the main force in stabilizing the RdRp-Remdesivir complex, while the van der Waals interaction dominates in the MproRemdesivir case. Our result indicates that Remdesivir can target not only RdRp but also Mpro, which can be invoked to explain why this drug is effective in treating Covid-19. We have identified residues of the target protein that make the most important contribution to binding affinity, and this information is useful for drug development for this disease. <br>

No abstract

In single-molecule force spectroscopy, the rupture force F max required for mechanical unfolding of a biomolecule or for pulling a ligand out of a binding site depends on the pulling speed V and, in the linear Bell–Evans regime, F max ∼ ln( V ). Recently, it has been found that non-equilibrium work W is better than F max in describing relative ligand binding affinity, but the dependence of W on V remains unknown. In this paper, we developed an analytical theory showing that in the linear regime, W ∼ c 1 ln( V ) + c 2 ln 2 ( V ), where c 1 and c 2 are constants. This quadratic dependence was also confirmed by all-atom steered molecular dynamics simulations of protein–ligand complexes. Although our theory was developed for ligand unbinding, it is also applicable to other processes, such as mechanical unfolding of proteins and other biomolecules, due to its universality.