Extracting consistent statistics between relevant free energy minima of a molecular system is essential for physics, chemistry, and biology. Molecular dynamics (MD) simulations can aid in this task but are computationally expensive, especially for systems that require quantum accuracy. To overcome this challenge, we developed an approach combining enhanced sampling with deep generative models and active learning of a machine learning potential (MLP).
View Article and Find Full Text PDFOur ability to calculate rate constants of biochemical processes using molecular dynamics simulations is severely limited by the fact that the time scales for reactions, or changes in conformational state, scale exponentially with the relevant free-energy barrier heights. In this work, we improve upon a recently proposed rate estimator that allows us to predict transition times with molecular dynamics simulations biased to rapidly explore one or several collective variables (CVs). This approach relies on the idea that not all bias goes into promoting transitions, and along with the rate, it estimates a concomitant scale factor for the bias termed the "CV biasing efficiency" γ.
View Article and Find Full Text PDFMolecular electronics break-junction experiments are widely used to investigate fundamental physics and chemistry at the nanoscale. Reproducibility in these experiments relies on measuring conductance on thousands of freshly formed molecular junctions, yielding a broad histogram of conductance events. Experiments typically focus on the most probable conductance, while the information content of the conductance histogram has remained unclear.
View Article and Find Full Text PDFSingle-particle cryo-electron microscopy (cryo-EM) is a technique that takes projection images of biomolecules frozen at cryogenic temperatures. A major advantage of this technique is its ability to image single biomolecules in heterogeneous conformations. While this poses a challenge for data analysis, recent algorithmic advances have enabled the recovery of heterogeneous conformations from the noisy imaging data.
View Article and Find Full Text PDFCryo-electron microscopy (cryo-EM) has recently become a leading method for obtaining high-resolution structures of biological macromolecules. However, cryo-EM is limited to biomolecular samples with low conformational heterogeneity, where most conformations can be well-sampled at various projection angles. While cryo-EM provides single-molecule data for heterogeneous molecules, most existing reconstruction tools cannot retrieve the ensemble distribution of possible molecular conformations from these data.
View Article and Find Full Text PDFThe aggregation of epitopes that are also able to bind major histocompatibility complex (MHC) alleles raises questions around the potential connection between the formation of epitope aggregates and their affinities to MHC receptors. We first performed a general bioinformatic assessment over a public dataset of MHC class II epitopes, finding that higher experimental binding correlates with higher aggregation-propensity predictors. We then focused on the case of P10, an epitope used as a vaccine candidate against that aggregates into amyloid fibrils.
View Article and Find Full Text PDFOmicron BA.1 is a highly infectious variant of SARS-CoV-2 that carries more than thirty mutations on the spike protein in comparison to the Wuhan wild type (WT). Some of the Omicron mutations, located on the receptor-binding domain (RBD), are exposed to the surrounding solvent and are known to help evade immunity.
View Article and Find Full Text PDFJ Comput Aided Mol Des
November 2022
Peptides are commonly used as therapeutic agents. However, they suffer from easy degradation and instability. Replacing natural by non-natural amino acids can avoid these problems, and potentially improve the affinity towards the target protein.
View Article and Find Full Text PDFSimulations with adaptive time-dependent bias enable an efficient exploration of the conformational space of a system. However, the dynamic information is altered by the bias. Infrequent metadynamics recovers the transition rate of crossing a barrier, if the collective variables are ideal and there is no bias deposition near the transition state.
View Article and Find Full Text PDFEpitopes that bind simultaneously to all human alleles of Major Histocompatibility Complex class II (MHC II) are considered one of the key factors for the development of improved vaccines and cancer immunotherapies. To engineer MHC II multiple-allele binders, we developed a protocol called PanMHC-PARCE, based on the unsupervised optimization of the epitope sequence by single-point mutations, parallel explicit-solvent molecular dynamics simulations and scoring of the MHC II-epitope complexes. The key idea is accepting mutations that not only improve the affinity but also reduce the affinity gap between the alleles.
View Article and Find Full Text PDFAb initio metadynamics enables the extraction of free-energy landscapes having the accuracy of first-principles electronic structure methods. We introduce an interface between the PLUMED code that computes free-energy landscapes and enhanced-sampling algorithms and the Atomic Simulation Environment (ASE) module, which includes several ab initio electronic structure codes. The interface is validated with a Lennard-Jones cluster free-energy landscape calculation by averaging multiple short metadynamics trajectories.
View Article and Find Full Text PDFComputational peptide design is useful for therapeutics, diagnostics, and vaccine development. To select the most promising peptide candidates, the key is describing accurately the peptide-target interactions at the molecular level. We here review a computational peptide design protocol whose key feature is the use of all-atom explicit solvent molecular dynamics for describing the different peptide-target complexes explored during the optimization.
View Article and Find Full Text PDFSeveral antimicrobial peptides, including magainin and the human cathelicidin LL-37, act by forming pores in bacterial membranes. Bacteria such as Staphylococcus aureus modify their membrane's cardiolipin composition to resist such types of perturbations that compromise their membrane stability. Here, we used molecular dynamic simulations to quantify the role of cardiolipin on the formation of pores in simple bacterial-like membrane models composed of phosphatidylglycerol and cardiolipin mixtures.
View Article and Find Full Text PDFTubulin is a well-validated target for herbicides, fungicides, anti-parasitic, and anti-tumor drugs. Many of the non-cancer tubulin drugs bind to its colchicine site but no colchicine-site anticancer drug is available. The colchicine site is composed of three interconnected sub-pockets that fit their ligands and modify others' preference, making the design of molecular hybrids (that bind to more than one sub-pocket) a difficult task.
View Article and Find Full Text PDFThe prediction of peptide binders to Major Histocompatibility Complex (MHC) class II receptors is of great interest to study autoimmune diseases and for vaccine development. Most approaches predict the affinities using sequence-based models trained on experimental data and multiple alignments from known peptide substrates. However, detecting activity differences caused by single-point mutations is a challenging task.
View Article and Find Full Text PDFCryo-electron microscopy (cryo-EM) extracts single-particle density projections of individual biomolecules. Although cryo-EM is widely used for 3D reconstruction, due to its single-particle nature it has the potential to provide information about a biomolecule's conformational variability and underlying free-energy landscape. However, treating cryo-EM as a single-molecule technique is challenging because of the low signal-to-noise ratio (SNR) in individual particles.
View Article and Find Full Text PDFPeptide research has increased during the last years due to their applications as biomarkers, therapeutic alternatives or as antigenic sub-units in vaccines. The implementation of computational resources have facilitated the identification of novel sequences, the prediction of properties, and the modelling of structures. However, there is still a lack of open source protocols that enable their straightforward analysis.
View Article and Find Full Text PDFBMC Bioinformatics
December 2020
Background: Proteases are key drivers in many biological processes, in part due to their specificity towards their substrates. However, depending on the family and molecular function, they can also display substrate promiscuity which can also be essential. Databases compiling specificity matrices derived from experimental assays have provided valuable insights into protease substrate recognition.
View Article and Find Full Text PDFNew treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia- by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available.
View Article and Find Full Text PDFCryo-electron microscopy (cryo-EM) has revolutionized structural biology by providing 3D density maps of biomolecules at near-atomic resolution. However, map validation is still an open issue. Despite several efforts from the community, it is possible to overfit 3D maps to noisy data.
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