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ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a large kinome profiling dataset, we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the other 398 kinases in the dataset. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 wit…

A protein is a dynamic shape-shifter whose function is determined by the set of structures it adopts. Unfortunately, atomically detailed structures are only available for a few conformations of any given protein, and these structures have limited explanatory and predictive power. Here, we provide a brief historical perspective on protein dynamics and introduce recent advances in computational and experimental methods that are providing unprecedented access to protein shape-shifting. Nex…

The dynamics of globular proteins can be described in terms of transitions between a folded native state and less-populated intermediates, or excited states, which can play critical roles in both protein folding and function. Excited states are by definition transient species, and therefore are difficult to characterize using current experimental techniques. Here, we report an atomistic model of the excited state ensemble of a stabilized mutant of an extensively studied flavodoxin fold …

We use reinforcement learning to train an agent for computational RNA design: given a target secondary structure, design a sequence that folds to that structure in silico. Our agent uses a novel graph convolutional architecture allowing a single model to be applied to arbitrary target structures of any length. After training it on randomly generated targets, we test it on the Eterna100 benchmark and find it outperforms all previous algorithms. Analysis of its solutions shows it has succ…

Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, mult…

Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transfer to another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with b…

While Langevin integrators are popular in the study of equilibrium properties of complex systems, it is challenging to estimate the timestep-induced discretization error: the degree to which the sampled phase-space or configuration-space probability density departs from the desired target density due to the use of a finite integration timestep. Sivak et al., introduced a convenient approach to approximating a natural measure of error between the sampled density and the target equilibriu…

Traditional approaches to specifying a molecular mechanics force field encode all the information needed to assign force field parameters to a given molecule into a discrete set of atom types. This is equivalent to a representation consisting of a molecular graph comprising a set of vertices, which represent atoms labeled by atom type, and unlabeled edges, which represent chemical bonds. Bond stretch, angle bend, and dihedral parameters are then assigned by looking up bonded pairs, trip…

Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically-detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of s…

Phenylalanine hydroxylase (PAH) regulates phenylalanine (Phe) levels in mammals to prevent neurotoxicity resulting from high Phe concentrations as observed in genetic disorders leading to hyperphenylalaninemia and phenylketonuria. PAH senses elevated Phe concentrations by transient allosteric Phe binding to a protein-protein interface between ACT domains of different subunits in a PAH tetramer. This interface is present in an activated PAH tetramer (A-PAH) and absent in a resting-state PAH tet…