Accurate prediction of the binding affinity of a protein-ligand complex is essential for efficient and successful rational drug design. Therefore, many binding affinity prediction methods have been developed. In recent years, since deep learning technology has become powerful, it is also implemented to predict affinity. In this work, a new neural network model that predicts the binding affinity of a protein-ligand complex structure is developed. Our model predicts the binding affinity of a complex using the ensemble of multiple independently trained networks that consist of multiple channels of 3-D convolutional neural network layers. Our model was trained using the 3772 protein-ligand complexes from the refined set of the PDBbind-2016 database and tested using the core set of 285 complexes. The benchmark results show that the Pearson correlation coefficient between the predicted binding affinities by our model and the experimental data is 0.827, which is higher than the state-of-the-art binding affinity prediction scoring functions. Additionally, our method ranks the relative binding affinities of possible multiple binders of a protein quite accurately, comparable to the other scoring functions. Last, we measured which structural information is critical for predicting binding affinity and found that the complementarity between the protein and ligand is most important.

Designing efficient synthetic routes for a target molecule remains a major challenge in organic synthesis. Atom environments are ideal, stand-alone, chemically meaningful building blocks providing a high-resolution molecular representation. Our approach mimics chemical reasoning, and predicts reactant candidates by learning the changes of atom environments associated with the chemical reaction. Through careful inspection of reactant candidates, we demonstrate atom environments as promising descriptors for studying reaction route prediction and discovery. Here, we present a new single-step retrosynthesis prediction method, viz. RetroTRAE, being free from all SMILES-based translation issues, yields a top-1 accuracy of 58.3% on the USPTO test dataset, and top-1 accuracy reaches to 61.6% with the inclusion of highly similar analogs, outperforming other state-of-the-art neural machine translation-based methods. Our methodology introduces a novel scheme for fragmental and topological descriptors to be used as natural inputs for retrosynthetic prediction tasks.

We present a new computational approach for constant pH simulations in explicit solvent based on the combination of the enveloping distribution sampling (EDS) and Hamiltonian replica exchange (HREX) methods. Unlike constant pH methods based on variable and continuous charge models, our method is based on discrete protonation states. EDS generates a hybrid Hamiltonian of different protonation states. A smoothness parameter s is used to control the heights of energy barriers of the hybrid-state energy landscape. A small s value facilitates state transitions by lowering energy barriers. Replica exchange between EDS potentials with different s values allows us to readily obtain a thermodynamically accurate ensemble of multiple protonation states with frequent state transitions. The analysis is performed with an ensemble obtained from an EDS Hamiltonian without smoothing, s = ∞, which strictly follows the minimum energy surface of the end states. The accuracy and efficiency of this method is tested on aspartic acid, lysine, and glutamic acid, which have two protonation states, a histidine with three states, a four-residue peptide with four states, and snake cardiotoxin with eight states. The pK_a values estimated with the EDS-HREX method agree well with the experimental pK_a values. The mean absolute errors of small benchmark systems range from 0.03 to 0.17 pK_a units, and those of three titratable groups of snake cardiotoxin range from 0.2 to 1.6 pK_a units. This study demonstrates that EDS-HREX is a potent theoretical framework, which gives the correct description of multiple protonation states and good calculated pK_a values.

Recently, predicting proteins three-dimensional (3D) structure from its sequence information has made a significant progress due to the advances in computational techniques and the growth of experimental structures. However, selecting good models from a structural model pool is an important and challenging task in protein structure prediction. In this study, we present the first application of random forest based model quality assessment (RFMQA) to rank protein models using its structural features and knowledge-based potential energy terms. The method predicts a relative score of a model by using its secondary structure, solvent accessibility and knowledge-based potential energy terms. We trained and tested the RFMQA method on CASP8 and CASP9 targets using 5-fold cross-validation. The correlation coefficient between the TM-score of the model selected by RFMQA (TM_RF) and the best server model (TM_best) is 0.945. We benchmarked our method on recent CASP10 targets by using CASP8 and 9 server models as a training set. The correlation coefficient and average difference between TM_RF and TM_best over 95 CASP10 targets are 0.984 and 0.0385, respectively. The test results show that our method works better in selecting top models when compared with other top performing methods. RFMQA is available for download from http://lee.kias.re.kr/RFMQA/RFMQA_eval.tar.gz.

Here, we introduce a new molecule optimization method, MolFinder, based on an efficient global optimization algorithm, the conformational space annealing algorithm, and the SMILES representation. MolFinder finds diverse molecules with desired properties efficiently without any training and a large molecular database. Compared with recently proposed reinforcement-learning-based molecule optimization algorithms, MolFinder consistently outperforms in terms of both the optimization of a given target property and the generation of a set of diverse and novel molecules. The efficiency of MolFinder demonstrates that combinatorial optimization using the SMILES representation is a promising approach for molecule optimization, which has not been well investigated despite its simplicity. We believe that our results shed light on new possibilities for advances in molecule optimization methods.

A bstract: In this preprint, we investigated whether AlphaFold2, AF2, can predict protein-peptide complex structures only with sequence information. We modeled the structures of 203 protein-peptide complexes from the PepBDB DB and 183 from the PepSet. The structures were modeling with concatenated sequences of receptors and peptides via poly-glycine linker. We found that for more than half of the test cases, AF2 predicted the bound structures of peptides with good accuracy, C α -RMSD of a peptide < 3.0 Å. For about 40% of cases, the peptide structures were modeled with an accuracy of C α -RMSD < 2.0 Å. Our benchmark results clearly show that AF2 has a great potential to be applied to various higher-order structure prediction tasks.