A critical comparison of general-purpose collective variables for crystal nucleation

The nucleation of crystals is a prominent phenomenon in science and technology that still lacks a full atomic-scale understanding. Much work has been devoted to identifying order parameters able to track the process, from the inception of early nuclei to their maturing to critical size until growth of an extended crystal. We critically assess and compare two powerful distance-based collective variables, an effective entropy derived from liquid state theory and the path variable based on permutation invariant vectors using the Kob-Andersen binary mixture and a combination of enhanced-sampling techniques. Our findings reveal a comparable ability to drive nucleation when a bias potential is applied, and comparable free-energy barriers and structural features. Yet, we also found an imperfect correlation with the committor probability on the barrier top which was bypassed by changing the order parameter definition

Optimal reaction coordinates and kinetic rates from the projected dynamics of transition paths

Finding optimal reaction coordinates and predicting accurate kinetic rates for activated processes are two of the foremost challenges of molecular simulations. We introduce an algorithm that tackles the two problems at once: starting from a limited number of reactive molecular dynamics trajectories (transition paths), we automatically generate with a Monte Carlo approach a sequence of different reaction coordinates that progressively reduce the kinetic rate of their projected effective dynamics. Based on a variational principle, the minimal rate accurately approximates the exact one, and it corresponds to the optimal reaction coordinate. After benchmarking the method on an analytic double-well system, we apply it to complex atomistic systems: the interaction of carbon nanoparticles of different sizes in water.Comment: 19 pages, 10 figure

Hydrothermal Decomposition of Amino Acids and Origins of Prebiotic Meteoritic Organic Compounds

The organic compounds found in carbonaceous chondrite meteorites provide insight into primordial solar system chemistry. Evaluating the formation and decomposition mechanisms of meteoritic amino acids may aid our understanding of the origins of life and homochirality on Earth. The amino acid glycine is widespread in meteorites and other extraterrestrial environments; other amino acids, such as isovaline, are found with enantiomeric excesses in some meteorites. The relationship between meteoritic amino acids and other compounds with similar molecular structures, such as aliphatic monoamines and monocarboxylic acids is unclear; experimental results evaluating the decomposition of amino acids have produced inconclusive results about the preferred pathways, reaction intermediates, and if the conditions applied may be compatible with those occurring inside meteoritic parent bodies. In this work, we performed extensive tandem metadynamics, umbrella sampling, and committor analysis to simulate the neutral mild hydrothermal decomposition mechanisms of glycine and isovaline and put them into context for the origins of meteoritic organic compounds. Our ab initio simulations aimed to determine free energy profiles and decomposition pathways for glycine and isovaline. We found that under our modeled conditions, methylammonium, glycolic acid, and sec-butylamine are the most likely decomposition products. These results suggest that meteoritic aliphatic monocarboxylic acids are not produced from decomposition of meteoritic amino acids. Our results also indicate that the decomposition of L-isovaline prefers an enantioselective pathway resulting in the production of (S)-sec-butylamine

Formic Acid Synthesis in a Water–Mineral System: Major Role of the Interface

Mineral surfaces are known for their catalytic properties, as they lower kinetic bar- riers to reactions, and modify chemical equilibria. Using ab-initio molecular dynamics and enhanced sampling methods we predict that the MgO(001)/water interface ther- modynamically favours the formation of formic acid from carbon monoxide and water. This occurs despite the lack of direct participation from the surface atoms, the reac- tion taking place beyond the first adsorbed layer. Furthermore, the application of an external electric field on the reaction in bulk water shows a similar effect. We propose that formic acid may be stabilised by the surface electric field, by direct comparison with the equilibrium in bulk water with and without an external electric field applied, and at the MgO(001)/water interface

Holo-like and Druggable Protein Conformations from Enhanced Sampling of Binding Pocket Volume and Shape

Understanding molecular recognition of small molecules by proteins in atomistic detail is key for drug design. Molecular docking is a widely used computational method to mimic ligand–protein association in silico. However, predicting conformational changes occurring in proteins upon ligand binding is still a major challenge. Ensemble docking approaches address this issue by considering a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g., molecular dynamics. However, holo structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the apo protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations called ensemble docking with enhanced sampling of pocket shape (EDES) that allows holo-like conformations of proteins to be generated by exploiting only their apo structures. This is achieved by defining a set of collective variables ..

Exploring the Universe of Protein Structures beyond the Protein Data Bank

It is currently believed that the atlas of existing protein structures is faithfully represented in the Protein Data Bank. However, whether this atlas covers the full universe of all possible protein structures is still a highly debated issue. By using a sophisticated numerical approach, we performed an exhaustive exploration of the conformational space of a 60 amino acid polypeptide chain described with an accurate all-atom interaction potential. We generated a database of around 30,000 compact folds with at least of secondary structure corresponding to local minima of the potential energy. This ensemble plausibly represents the universe of protein folds of similar length; indeed, all the known folds are represented in the set with good accuracy. However, we discover that the known folds form a rather small subset, which cannot be reproduced by choosing random structures in the database. Rather, natural and possible folds differ by the contact order, on average significantly smaller in the former. This suggests the presence of an evolutionary bias, possibly related to kinetic accessibility, towards structures with shorter loops between contacting residues. Beside their conceptual relevance, the new structures open a range of practical applications such as the development of accurate structure prediction strategies, the optimization of force fields, and the identification and design of novel folds

PLUMED: a portable plugin for free-energy calculations with molecular dynamics

Here we present a program aimed at free-energy calculations in molecular systems. It consists of a series of routines that can be interfaced with the most popular classical molecular dynamics (MD) codes through a simple patching procedure. This leaves the possibility for the user to exploit many different MD engines depending on the system simulated and on the computational resources available. Free-energy calculations can be performed as a function of many collective variables, with a particular focus on biological problems, and using state-of-the-art methods such as metadynamics, umbrella sampling and Jarzynski-equation based steered MD. The present software, written in ANSI-C language, can be easily interfaced with both fortran and C/C++ codes.Comment: to be submitted to Computer Physics Communication