Conventional de novo drug design is time consuming, laborious, and resource intensive. In recent years, emerging in silico approaches have been proven to be critical to accelerate the process of ...bringing drugs to market. Molecular dynamics (MD) simulations of single molecule and molecular complexes have been commonly applied to achieve accurate binding modes and binding energies of drug-receptor interactions. A derivative of MD, namely, steered molecular dynamics (SMD), has been demonstrated as a promising tool for rational drug design. In this paper, we review various studies over the last 20 years using SMD simulations, thus paving the way to determine the relationship between protein structure and function. In addition, the paper highlights the use of SMD simulation for in silico drug design. We also aim to establish an understanding on the key interactions which play a crucial role in the stabilization of peptide–ligand interfaces, the binding and unbinding mechanism of the ligand–protein complex, the mechanism of ligand translocating via membrane, and the ranking of different ligands on receptors as therapeutic candidates.
Accelerated molecular-dynamics (MD) simulations based on hyperdynamics (HD) can significantly improve the efficiency of MD simulations of condensed-phase systems that evolve via rare events. However, ...such simulations are not generally easy to apply since appropriate boosts are usually unknown. In this work, we developed a method called OptiBoost to adjust the value of the boost in HD simulations based on the bond-boost method. We demonstrated the OptiBoost method in simulations on a cosine potential and applied it in three different systems involving Ag diffusion on Ag(100) in vacuum and in ethylene glycol solvent. In all cases, OptiBoost was able to predict safe and effective values of the boost, indicating that the OptiBoost protocol is an effective way to advance the applicability of HD simulations.
The microstructure of a mixed KCl and Ksub.2SOsub.4 aqueous solution was studied using X-ray scattering (XRS), Raman spectroscopy, and molecular dynamics simulation (MD). Reduced structure functions ...F(Q), reduced pair distribution functions G(r), Raman spectrum, and pair distribution functions (PDF) were obtained. The XRS results show that the main peak (r = 2.81 Å) of G(r) shifted to the right of the axis (r = 3.15 Å) with increased KCl and decreased Ksub.2SOsub.4. The main peak was at r = 3.15 Å when the KCl concentration was 26.00% and the Ksub.2SOsub.4 concentration was 0.00%. It is speculated that this phenomenon was caused by the main interaction changing, from K-Osub.W (r = 2.80 Å) and Osub.W-Osub.W (r = 2.80 Å), to Clsup.−-Osub.W (r = 3.14 Å) and Ksup.+-Clsup.− (r = 3.15 Å). According to the trend of the hydrogen bond structure in the Raman spectrum, when the concentration of KCl was high and Ksub.2SOsub.4 was low, the destruction of the tetrahedral hydrogen bond network in the solution was more serious. This shows that the destruction strength of the anion to the hydrogen bond network structure in solution was Clsup.− > SOsub.4 sup.2−. In the MD simulations, the coordination number of Osub.W-Osub.W decreased with increasing KCl concentration, indicating that the tetrahedral hydrogen bond network was severely disrupted, which confirmed the results of the Raman spectroscopy. The hydration radius and coordination number of SOsub.4 sup.2− in the mixed solution were larger than Clsup.−, thus revealing the reason why the solubility of KCl in water was greater than that of Ksub.2SOsub.4 at room temperature.
The temperature‐dependent properties of the aqueous electron have been extensively studied using mixed quantum‐classical simulations in a wide range of thermodynamic conditions based on one‐electron ...pseudopotentials. While the cavity model appears to explain most of the physical properties of the aqueous electron, only a non‐cavity model has so far been successful in accounting for the temperature dependence of the absorption spectrum. Here, we present an accurate and efficient description of the aqueous electron under various thermodynamic conditions by combining hybrid functional‐based molecular dynamics, machine learning techniques, and multiple time‐step methods. Our advanced simulations accurately describe the temperature dependence of the absorption maximum in the presence of cavity formation. Specifically, our work reveals that the red shift of the absorption maximum results from an increasing gyration radius with temperature, rather than from global density variations as previously suggested.
Ab initio molecular dynamics simulations of the aqueous electron in various thermodynamic conditions at the accuracy of hybrid functional electronic structure theory are reported. This work reveals that the red shift of the absorption maximum results from an increasing gyration radius with temperature.
Fully understanding the mechanisms of signaling proteins such as G protein-coupled receptors (GPCRs) will require the characterization of their conformational states and the pathways connecting those ...states. The recent crystal structures of the β
2
- and β
1
-adrenergic receptors in a nominally inactive state constituted a major advance toward this goal, but also raised new questions. Although earlier biochemical observations had suggested that these receptors possessed a set of contacts between helices 3 and 6, known as the ionic lock, which was believed to form a molecular switch for receptor activation, the crystal structures lacked these contacts. The unexpectedly broken ionic lock has raised questions about the true conformation(s) of the inactive state and the role of the ionic lock in receptor activation and signaling. To address these questions, we performed microsecond-timescale molecular dynamics simulations of the β
2
-adrenergic receptor (β
2
AR) in multiple wild-type and mutant forms. In wild-type simulations, the ionic lock formed reproducibly, bringing the intracellular ends of helices 3 and 6 together to adopt a conformation similar to that found in inactive rhodopsin. Our results suggest that inactive β
2
AR exists in equilibrium between conformations with the lock formed and the lock broken, whether or not the cocrystallized ligand is present. These findings, along with the formation of several secondary structural elements in the β
2
AR loops during our simulations, may provide a more comprehensive picture of the inactive state of the β-adrenergic receptors, reconciling the crystal structures with biochemical studies.
In this paper, we report the changes in structural and dynamical properties of a MgSiO.sub.3 liquid under compression via molecular dynamics simulation. The short-range order is analyzed through the ...bond angles and bond lengths of the structural units, and the mean coordination number of both Si and Mg metals is found to increase with pressure. Intermediate-range order, characterized by the number of OT.sub.y links and of corner-, edge- and face-sharing bonds between two neighboring units, suggests the formation of Si-O- and Mg-O-rich regions in the magnesium silicate liquid. The self-diffusion and viscosity coefficients are then calculated to characterize the system dynamics and are found to be in good agreement with previous experiments and simulations. Most importantly, our result suggests a relationship between structural and dynamic heterogeneity of liquid magnesium silicates, particularly at high pressure. Graphical abstract
Enzyme‐powered micro/nanomotors have myriads of potential applications in various areas. To efficiently reach those applications, it is necessary and critical to understand the fundamental aspects ...affecting the motion dynamics. Herein, we explored the impact of enzyme orientation on the performance of lipase‐powered nanomotors by tuning the lipase immobilization strategies. The influence of the lipase orientation and lid conformation on substrate binding and catalysis was analyzed using molecular dynamics simulations. Besides, the motion performance indicates that the hydrophobic binding (via OTES) represents the best orienting strategy, providing 48.4 % and 95.4 % increase in diffusion coefficient compared to hydrophilic binding (via APTES) and Brownian motion (no fuel), respectively (with Ctriacetin of 100 mm). This work provides vital evidence for the importance of immobilization strategy and corresponding enzyme orientation for the catalytic activity and in turn, the motion performance of nanomotors, and is thus helpful to future applications.
The impact of enzyme orientation on the performance of lipase‐powered nanomotors was explored and analysed, indicating that hydrophobic interaction is the best strategy for immobilizing lipase to provide high‐efficiency catalysis. This results in high‐efficiency enhanced Brownian motion, which would be vital in promoting the future applications of enzyme‐powered micro/nanomotors.
An increasingly important endeavor is to develop computational strategies that enable molecular dynamics (MD) simulations of biomolecular systems with spontaneous changes in protonation states under ...conditions of constant pH. The present work describes our efforts to implement the powerful constant-pH MD simulation method, based on a hybrid nonequilibrium MD/Monte Carlo (neMD/MC) technique within the highly scalable program NAMD. The constant-pH hybrid neMD/MC method has several appealing features; it samples the correct semigrand canonical ensemble rigorously, the computational cost increases linearly with the number of titratable sites, and it is applicable to explicit solvent simulations. The present implementation of the constant-pH hybrid neMD/MC in NAMD is designed to handle a wide range of biomolecular systems with no constraints on the choice of force field. Furthermore, the sampling efficiency can be adaptively improved on-the-fly by adjusting algorithmic parameters during the simulation. Illustrative examples emphasizing medium- and large-scale applications on next-generation supercomputing architectures are provided.
Receptor–ligand interactions are essential for biological function and their binding strength is commonly explained in terms of static lock-and-key models based on molecular complementarity. However, ...detailed information on the full unbinding pathway is often lacking due, in part, to the static nature of atomic structures and ensemble averaging inherent to bulk biophysics approaches. Here we combine molecular dynamics and high-speed force spectroscopy on the streptavidin–biotin complex to determine the binding strength and unbinding pathways over the widest dynamic range. Experiment and simulation show excellent agreement at overlapping velocities and provided evidence of the unbinding mechanisms. During unbinding, biotin crosses multiple energy barriers and visits various intermediate states far from the binding pocket, while streptavidin undergoes transient induced fits, all varying with loading rate. This multistate process slows down the transition to the unbound state and favors rebinding, thus explaining the long lifetime of the complex. We provide an atomistic, dynamic picture of the unbinding process, replacing a simple two-state picture with one that involves many routes to the lock and ratedependent induced-fit motions for intermediates, which might be relevant for other receptor–ligand bonds.
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