Flexible Topology: A Dynamic Model of a Continuous Chemical Space.

Ligand design problems involve searching chemical space for a molecule with a set of desired properties. As chemical space is discrete, this search must be conducted in a pointwise manner, separately investigating one molecule at a time, which can be inefficient. We propose a method called "Flexible Topology", where a ligand is composed of a set of shapeshifting "ghost" atoms, whose atomic identities and connectivity can dynamically change over the course of a simulation. Ghost atoms are guided toward their target positions using a translation-, rotation-, and index-invariant restraint potential. This is the first step toward a continuous model of chemical space, where a dynamic simulation can move from one molecule to another by following gradients of a potential energy function. This builds on a substantial history of alchemy in the field of molecular dynamics simulation, including the Lambda dynamics method developed by Brooks and co-workers [X. Kong and C.L. Brooks III, J. Chem. Phys. 105, 2414 (1996)], but takes it to an extreme by associating a set of four dynamical attributes with each shapeshifting ghost atom that control not only its presence but also its atomic identity. Here, we outline the theoretical details of this method, its implementation using the OpenMM simulation package, and some preliminary studies of ghost particle assembly simulations in vacuum. We examine a set of 10 small molecules, ranging in size from 6 to 50 atoms, and show that Flexible Topology is able to consistently assemble all of these molecules to high accuracy, beginning from randomly initialized positions and attributes.

Predicting partition coefficients for the SAMPL7 physical property challenge using the ClassicalGSG method.

The prediction of [Formula: see text] values is one part of the statistical assessment of the modeling of proteins and ligands (SAMPL) blind challenges. Here, we use a molecular graph representation method called Geometric Scattering for Graphs (GSG) to transform atomic attributes to molecular features. The atomic attributes used here are parameters from classical molecular force fields including partial charges and Lennard-Jones interaction parameters. The molecular features from GSG are used as inputs to neural networks that are trained using a "master" dataset comprised of over 41,000 unique [Formula: see text] values. The specific molecular targets in the SAMPL7 [Formula: see text] prediction challenge were unique in that they all contained a sulfonyl moeity. This motivated a set of ClassicalGSG submissions where predictors were trained on different subsets of the master dataset that are filtered according to chemical types and/or the presence of the sulfonyl moeity. We find that our ranked prediction obtained 5th place with an RMSE of 0.77 [Formula: see text] units and an MAE of 0.62, while one of our non-ranked predictions achieved first place among all submissions with an RMSE of 0.55 and an MAE of 0.44. After the conclusion of the challenge we also examined the performance of open-source force field parameters that allow for an end-to-end [Formula: see text] predictor model: General AMBER Force Field (GAFF), Universal Force Field (UFF), Merck Molecular Force Field 94 (MMFF94) and Ghemical. We find that ClassicalGSG models trained with atomic attributes from MMFF94 can yield more accurate predictions compared to those trained with CGenFF atomic attributes.

ClassicalGSG: Prediction of log P using classical molecular force fields and geometric scattering for graphs.

This work examines methods for predicting the partition coefficient (log P) for a dataset of small molecules. Here, we use atomic attributes such as radius and partial charge, which are typically used as force field parameters in classical molecular dynamics simulations. These atomic attributes are transformed into index-invariant molecular features using a recently developed method called geometric scattering for graphs (GSG). We call this approach "ClassicalGSG" and examine its performance under a broad range of conditions and hyperparameters. We train ClassicalGSG log P predictors with neural networks using 10,722 molecules from the OpenChem dataset and apply them to predict the log P values from four independent test sets. The ClassicalGSG method's performance is compared to a baseline model that employs graph convolutional networks. Our results show that the best prediction accuracies are obtained using atomic attributes generated with the CHARMM generalized force field and 2D molecular structures.

REVO: Resampling of ensembles by variation optimization.

Conventional molecular dynamics simulations are incapable of sampling many important interactions in biomolecular systems due to their high dimensionality and rough energy landscapes. To observe rare events and calculate transition rates in these systems, enhanced sampling is a necessity. In particular, the study of ligand-protein interactions necessitates a diverse ensemble of protein conformations and transition states, and for many systems, this occurs on prohibitively long time scales. Previous strategies such as WExplore that can be used to determine these types of ensembles are hindered by problems related to the regioning of conformational space. Here, we propose a novel, regionless, enhanced sampling method that is based on the weighted ensemble framework. In this method, a value referred to as "trajectory variation" is optimized after each cycle through cloning and merging operations. This method allows for a more consistent measurement of observables and broader sampling resulting in the efficient exploration of previously unexplored conformations. We demonstrate the performance of this algorithm with the N-dimensional random walk and the unbinding of the trypsin-benzamidine system. The system is analyzed using conformation space networks, the residence time of benzamidine is confirmed, and a new unbinding pathway for the trypsin-benzamidine system is found. We expect that resampling of ensembles by variation optimization will be a useful general tool to broadly explore free energy landscapes.

Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ.

Signaling molecule phosphatidylinositol 4,5-bisphosphate is produced primarily by phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is essential for the development of the human neuronal system, which has been exemplified by a recessive genetic disorder, lethal congenital contractural syndrome type 3, caused by a single aspartate-to-asparagine mutation in the kinase domain of PIP5Kγ. So far, the exact role of this aspartate residue has yet to be elucidated. In this work, we conducted structural, functional and computational studies on a zebrafish PIP5Kα variant with a mutation at the same site. Compared with the structure of the wild-type (WT) protein in the ATP-bound state, the ATP-associating glycine-rich loop of the mutant protein was severely disordered and the temperature factor of ATP was significantly higher. Both observations suggest a greater degree of disorder of the bound ATP, whereas neither the structure of the catalytic site nor the Km toward ATP was substantially affected by the mutation. Microsecond molecular dynamics simulation revealed that negative charge elimination caused by the mutation destabilized the involved hydrogen bonds and affected key electrostatic interactions in the close proximity of ATP. Taken together, our data indicated that the disease-related aspartate residue is a key node in the interaction network crucial for effective ATP binding. This work provides a paradigm of how a subtle but critical structural perturbation caused by a single mutation at the ATP-binding site abolishes the kinase activity, emphasizing that stabilizing substrate in a productive conformational state is crucial for catalysis.