More is simpler: Decomposition of ligand-binding affinity for proteins being disordered.

In statistical mechanics, it is well known that the huge number of degrees of freedom does not complicate the problem as it seems, but actually greatly simplifies the analysis (e.g., to give a Boltzmann distribution). Here, we reveal that the ensemble averaging from the vast conformations of intrinsically disordered proteins (IDPs) greatly simplifies the nature of binding affinity, which can be reliably decomposed into a sum of the ligandability of IDP and the capacity of ligand. Such an unexpected regularity is applied to facilitate the virtual screening upon IDPs. It also provides essential insight in understanding the specificity difference between IDPs and conventional ordered proteins since the specificity is caused by deviation from the baseline behavior of protein-ligand binding.

Reinforcement learning to boost molecular docking upon protein conformational ensemble.

Intrinsically disordered proteins (IDPs) are widely involved in human diseases and thus are attractive therapeutic targets. In practice, however, it is computationally prohibitive to dock large ligand libraries to thousands and tens of thousands of conformations. Here, we propose a reversible upper confidence bound (UCB) algorithm for the virtual screening of IDPs to address the influence of the conformation ensemble. The docking process is dynamically arranged so that attempts are focused near the boundary to separate top ligands from the bulk accurately. It is demonstrated in the example of transcription factor c-Myc that the average docking number per ligand can be greatly reduced while the performance is merely slightly affected. This study suggests that reinforcement learning is highly efficient in solving the bottleneck of virtual screening due to the conformation ensemble in the rational drug design of IDPs.

Ensemble-Based Thermodynamics of the Fuzzy Binding between Intrinsically Disordered Proteins and Small-Molecule Ligands.

In contrast to the "lock-and-key" model underlying the long-term success of structural biology and rational drug design, intrinsically disordered proteins (IDPs) exist in an ensemble of highly heterogeneous conformations even after binding with small-molecule ligands. It remains controversial how to characterize the thermodynamics of such fuzzy interactions. Here, we derive an ensemble-based thermodynamic framework to analyze the apparent affinity between IDPs and ligands. It is shown that the apparent affinity is related to the interaction free energy between the individual conformation and ligand in a way similar to Jarzynski's equality in nonequilibrium statistics. The oncoprotein c-Myc is adopted as an example to demonstrate the related properties, for example, the distribution of conformation-ligand interaction free energy, the entropic contribution from the ensemble, the conformation shift under ligand binding, and how to control the error under a limited number of sampled conformations.

[Study on process and principle of lactose grinding modification to decrease hygroscopic of Rhodiolae Crenulatae Radix et Rhizoma extract].

In this paper, Rhodiolae Crenulatae Radix et Rhizoma extract,with high hygroscopic,was selected as research model, while lactose was selected as modifiers to study the effect of the grinding modification method on the hygroscopic. Subsequently, particle size distribution, scannin electron microscopy, infrared spectroscopy and surface properties were adopted for a phase analysis. The results showed that the modified extract, prepared by Rhodiolae Crenulatae Radix et Rhizoma extract grinding 5 min with the same amount of lactose UP2, which hygroscopic initial velocity, acceleration, and critical relative humidity moisture were less than that of Rhodiolae Crenulatae Radix et Rhizoma extract and the mixture dramatically. In addition, compared with the mixture, the size distribution of modified extract was much less, the microstructure was also difference, while the infrared spectroscopy and surface properties were similar with that of lactose. It is the main principle that lactose particle adhered to the surface of Rhodiolae Crenulatae Radix et Rhizoma extract after grinding mofication to decress the moisture obviously.