Classification of complex local environments in systems of particle shapes through shape symmetry-encoded data augmentation.

Detecting and analyzing the local environment is crucial for investigating the dynamical processes of crystal nucleation and shape colloidal particle self-assembly. Recent developments in machine learning provide a promising avenue for better order parameters in complex systems that are challenging to study using traditional approaches. However, the application of machine learning to self-assembly on systems of particle shapes is still underexplored. To address this gap, we propose a simple, physics-agnostic, yet powerful approach that involves training a multilayer perceptron (MLP) as a local environment classifier for systems of particle shapes, using input features such as particle distances and orientations. Our MLP classifier is trained in a supervised manner with a shape symmetry-encoded data augmentation technique without the need for any conventional roto-translations invariant symmetry functions. We evaluate the performance of our classifiers on four different scenarios involving self-assembly of cubic structures, two-dimensional and three-dimensional patchy particle shape systems, hexagonal bipyramids with varying aspect ratios, and truncated shapes with different degrees of truncation. The proposed training process and data augmentation technique are both straightforward and flexible, enabling easy application of the classifier to other processes involving particle orientations. Our work thus presents a valuable tool for investigating self-assembly processes on systems of particle shapes, with potential applications in structure identification of any particle-based or molecular system where orientations can be defined.

Driving and characterizing nucleation of urea and glycine polymorphs in water.

Crystal nucleation is relevant across the domains of fundamental and applied sciences. However, in many cases, its mechanism remains unclear due to a lack of temporal or spatial resolution. To gain insights into the molecular details of nucleation, some form of molecular dynamics simulations is typically performed; these simulations, in turn, are limited by their ability to run long enough to sample the nucleation event thoroughly. To overcome the timescale limits in typical molecular dynamics simulations in a manner free of prior human bias, here, we employ the machine learning-augmented molecular dynamics framework "reweighted autoencoded variational Bayes for enhanced sampling (RAVE)." We study two molecular systems-urea and glycine-in explicit all-atom water, due to their enrichment in polymorphic structures and common utility in commercial applications. From our simulations, we observe multiple back-and-forth nucleation events of different polymorphs from homogeneous solution; from these trajectories, we calculate the relative ranking of finite-sized polymorph crystals embedded in solution, in terms of the free-energy difference between the finite-sized crystal polymorph and the original solution state. We further observe that the obtained reaction coordinates and transitions are highly nonclassical.

Path sampling of recurrent neural networks by incorporating known physics.

Recurrent neural networks have seen widespread use in modeling dynamical systems in varied domains such as weather prediction, text prediction and several others. Often one wishes to supplement the experimentally observed dynamics with prior knowledge or intuition about the system. While the recurrent nature of these networks allows them to model arbitrarily long memories in the time series used in training, it makes it harder to impose prior knowledge or intuition through generic constraints. In this work, we present a path sampling approach based on principle of Maximum Caliber that allows us to include generic thermodynamic or kinetic constraints into recurrent neural networks. We show the method here for a widely used type of recurrent neural network known as long short-term memory network in the context of supplementing time series collected from different application domains. These include classical Molecular Dynamics of a protein and Monte Carlo simulations of an open quantum system continuously losing photons to the environment and displaying Rabi oscillations. Our method can be easily generalized to other generative artificial intelligence models and to generic time series in different areas of physical and social sciences, where one wishes to supplement limited data with intuition or theory based corrections.

Toward Automated Sampling of Polymorph Nucleation and Free Energies with the SGOOP and Metadynamics.

Understanding the driving forces behind the nucleation of different polymorphs is of great importance for material sciences and the pharmaceutical industry. This includes understanding the reaction coordinate that governs the nucleation process and correctly calculating the relative free energies of different polymorphs. Here, we demonstrate, for the prototypical case of urea nucleation from the melt, how one can learn such a one-dimensional reaction coordinate as a function of prespecified order parameters and use it to perform efficient biased all-atom molecular dynamics simulations. The reaction coordinate is learnt as a function of the generic thermodynamic and structural order parameters using the "spectral gap optimization of order parameters (SGOOP)" approach [Tiwary, P. and Berne, B. J. Proc. Natl. Acad. Sci. U.S.A. (2016)] and is biased using well-tempered metadynamics simulations. The reaction coordinate gives insights into the role played by different structural and thermodynamics order parameters, and the biased simulations obtain accurate relative free energies for different polymorphs. This includes an accurate prediction of the approximate pressure at which urea undergoes a phase transition and one of the metastable polymorphs becomes the most stable conformation. We believe the ideas demonstrated in this work will facilitate efficient sampling of nucleation in complex, generic systems.

SGOOP-d: Estimating Kinetic Distances and Reaction Coordinate Dimensionality for Rare Event Systems from Biased/Unbiased Simulations.

Understanding kinetics including reaction pathways and associated transition rates is an important yet difficult problem in numerous chemical and biological systems, especially in situations with multiple competing pathways. When these high-dimensional systems are projected on low-dimensional coordinates, which are often needed for enhanced sampling or for interpretation of simulations and experiments, one can end up losing the kinetic connectivity of the underlying high-dimensional landscape. Thus, in the low-dimensional projection, metastable states might appear closer or further than they actually are. To deal with this issue, in this work, we develop a formalism that learns a multidimensional yet minimally complex reaction coordinate (RC) for generic high-dimensional systems. When projected along this RC, all possible kinetically relevant pathways can be demarcated and the true high-dimensional connectivity is maintained. One of the defining attributes of our method lies in that it can work on long unbiased simulations as well as biased simulations often needed for rare event systems. We demonstrate the utility of the method by studying a range of model systems including conformational transitions in a small peptide Ace-Ala3-Nme, where we show how two-dimensional and three-dimensional RCs found by our previously published spectral gap optimization method "SGOOP" [Tiwary, P. and Berne, B. J. Proc. Natl. Acad. Sci. 2016, 113, 2839] can capture the kinetics for 23 and all 28 out of the 28 dominant state-to-state transitions, respectively.

Learning molecular dynamics with simple language model built upon long short-term memory neural network.

Recurrent neural networks have led to breakthroughs in natural language processing and speech recognition. Here we show that recurrent networks, specifically long short-term memory networks can also capture the temporal evolution of chemical/biophysical trajectories. Our character-level language model learns a probabilistic model of 1-dimensional stochastic trajectories generated from higher-dimensional dynamics. The model captures Boltzmann statistics and also reproduces kinetics across a spectrum of timescales. We demonstrate how training the long short-term memory network is equivalent to learning a path entropy, and that its embedding layer, instead of representing contextual meaning of characters, here exhibits a nontrivial connectivity between different metastable states in the underlying physical system. We demonstrate our model's reliability through different benchmark systems and a force spectroscopy trajectory for multi-state riboswitch. We anticipate that our work represents a stepping stone in the understanding and use of recurrent neural networks for understanding the dynamics of complex stochastic molecular systems.

Crumpling-origami transition for twisting cylindrical shells.

Origami and crumpling are two processes to reduce the size of a membrane. In the shrink-expand process, the crease pattern of the former is ordered and protected by its topological mechanism, while that of the latter is disordered and generated randomly. We observe a morphological transition between origami and crumpling states in a twisted cylindrical shell. By studying the regularity of the crease pattern, acoustic emission, and energetics from experiments and simulations, we develop a model to explain this transition from frustration of geometry that causes breaking of rotational symmetry. In contrast to solving von Kármán-Donnell equations numerically, our model allows derivations of analytic formulas that successfully describe the origami state. When generalized to truncated cones and polygonal cylinders, we explain why multiple and/or reversed crumpling-origami transitions can occur.

Reaction coordinates and rate constants for liquid droplet nucleation: Quantifying the interplay between driving force and memory.

In this work, we revisit the classic problem of homogeneous nucleation of a liquid droplet in a supersaturated vapor phase. We consider this at different extents of the driving force, or equivalently the supersaturation, and calculate a reaction coordinate (RC) for nucleation as the driving force is varied. The RC is constructed as a linear combination of three order parameters, where one accounts for the number of liquidlike atoms and the other two for local density fluctuations. The RC is calculated from biased and unbiased molecular dynamics (MD) simulations using the spectral gap optimization approach "SGOOP" [P. Tiwary and B. J. Berne, Proc. Natl. Acad. Sci. U. S. A. 113, 2839 (2016)]. Our key finding is that as the supersaturation decreases, the RC ceases to simply be the number of liquidlike atoms, and instead, it becomes important to explicitly consider local density fluctuations that correlate with shape and density variations in the nucleus. All three order parameters are found to have similar barriers in their respective potentials of mean force; however, as the supersaturation decreases, the density fluctuations decorrelate slower and thus carry longer memory. Thus, at lower supersaturations, density fluctuations are non-Markovian and cannot be simply ignored from the RC by virtue of being noise. Finally, we use this optimized RC to calculate nucleation rates in the infrequent metadynamics framework and show that it leads to a more accurate estimate of the nucleation rate with four orders of magnitude acceleration relative to unbiased MD.

Kinetics of Ligand-Protein Dissociation from All-Atom Simulations: Are We There Yet?

Large parallel gains in the development of both computational resources and sampling methods have now made it possible to simulate dissociation events in ligand-protein complexes with all-atom resolution. Such encouraging progress, together with the inherent spatiotemporal resolution associated with molecular simulations, has left their use for investigating dissociation processes brimming with potential, both in rational drug design, where it can be an invaluable tool for determining the mechanistic driving forces behind dissociation rate constants, and in force-field development, where it can provide a catalog of transient molecular structures with which to refine force fields. Although much progress has been made in making force fields more accurate, reducing their error for transient structures along a transition path could yet prove to be a critical development helping to make kinetic predictions much more accurate. In what follows, we will provide a state-of-the-art compilation of the enhanced sampling methods based on molecular dynamics (MD) simulations used to investigate the kinetics and mechanisms of ligand-protein dissociation processes. Due to the time scales of such processes being slower than what is accessible using straightforward MD simulations, several ingenious schemes are being devised at a rapid rate to overcome this obstacle. Here we provide an up-to-date compendium of such methods and their achievements and shortcomings in extracting mechanistic insight into ligand-protein dissociation. We conclude with a critical and provocative appraisal attempting to answer the title of this Perspective.

Multi-dimensional spectral gap optimization of order parameters (SGOOP) through conditional probability factorization.

Spectral gap optimization of order parameters (SGOOP) [P. Tiwary and B. J. Berne, Proc. Natl. Acad. Sci. U. S. A. 113, 2839 (2016)] is a method for constructing the reaction coordinate (RC) in molecular systems, especially when they are plagued with hard to sample rare events, given a larger dictionary of order parameters or basis functions and limited static and dynamic information about the system. In its original formulation, SGOOP is designed to construct a 1-dimensional RC. Here we extend its scope by introducing a simple but powerful extension based on the notion of conditional probability factorization where known features are effectively washed out to learn additional and possibly hidden features of the energy landscape. We show how SGOOP can be used to proceed in a sequential and bottom-up manner to (i) systematically probe the need for extending the dimensionality of the RC and (ii) if such a need is identified, learn additional coordinates of the RC in a computationally efficient manner. We formulate the method and demonstrate its utility through three illustrative examples, including the challenging and important problem of calculating the kinetics of benzene unbinding from the protein T4L99A lysozyme, where we obtain excellent agreement in terms of dissociation pathway and kinetics with other sampling methods and experiments. In this last case, starting from a larger dictionary of 11 order parameters that are generic for ligand unbinding processes, we demonstrate how to automatically learn a 2-dimensional RC, which we then use in the infrequent metadynamics protocol to obtain 16 independent unbinding trajectories. We believe our method will be a big step in increasing the utility of SGOOP in performing intuition-free sampling of complex systems. Finally, we believe that the utility of our protocol is amplified by its applicability to not just SGOOP but also other generic methods for constructing the RC.

Acoustic Emission from Breaking a Bamboo Chopstick.

The acoustic emission from breaking a bamboo chopstick or a bundle of spaghetti is found to exhibit similar behavior as the famous seismic laws of Gutenberg and Richter, Omori, and Båth. By the use of a force-sensing detector, we establish a positive correlation between the statistics of sound intensity and the magnitude of a tremor. We also manage to derive these laws analytically without invoking the concept of a phase transition, self-organized criticality, or fractal. Our model is deterministic and relies on the existence of a structured cross section, either fibrous or layered. This success at explaining the power-law behavior supports the proposal that geometry is sometimes more important than mechanics.

Power-law ansatz in complex systems: Excessive loss of information.

The ubiquity of power-law relations in empirical data displays physicists' love of simple laws and uncovering common causes among seemingly unrelated phenomena. However, many reported power laws lack statistical support and mechanistic backings, not to mention discrepancies with real data are often explained away as corrections due to finite size or other variables. We propose a simple experiment and rigorous statistical procedures to look into these issues. Making use of the fact that the occurrence rate and pulse intensity of crumple sound obey a power law with an exponent that varies with material, we simulate a complex system with two driving mechanisms by crumpling two different sheets together. The probability function of the crumple sound is found to transit from two power-law terms to a bona fide power law as compaction increases. In addition to showing the vicinity of these two distributions in the phase space, this observation nicely demonstrates the effect of interactions to bring about a subtle change in macroscopic behavior and more information may be retrieved if the data are subject to sorting. Our analyses are based on the Akaike information criterion that is a direct measurement of information loss and emphasizes the need to strike a balance between model simplicity and goodness of fit. As a show of force, the Akaike information criterion also found the Gutenberg-Richter law for earthquakes and the scale-free model for a brain functional network, a two-dimensional sandpile, and solar flare intensity to suffer an excessive loss of information. They resemble more the crumpled-together ball at low compactions in that there appear to be two driving mechanisms that take turns occurring.