Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design.

Targeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into proximity.

Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods.

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with protein inhibition. Recent advancements in the biotech and pharmaceutical sectors have led to the development of compounds that are currently in human trials, with some showing promising clinical results. However, the use of computational tools in TPD is still limited, as it has distinct characteristics compared with traditional computational drug design methods.

A Conserved Local Structural Motif Controls the Kinetics of PTP1B Catalysis.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin signaling pathways, making it a highly attractive target for the treatment of type II diabetes. For PTP1B to perform its enzymatic function, a loop referred to as the "WPD loop" must transition between open (catalytically incompetent) and closed (catalytically competent) conformations, which have both been resolved by X-ray crystallography. Although prior studies have established this transition as the rate-limiting step for catalysis, the transition mechanism for PTP1B and other PTPs has been unclear.

Molecular Latent Space Simulators for Distributed and Multimolecular Trajectories.

All atom molecular dynamics (MD) simulations offer a powerful tool for molecular modeling, but the short time steps required for numerical stability of the integrator place many interesting molecular events out of reach of unbiased simulations. The popular and powerful Markov state modeling (MSM) approach can extend these time scales by stitching together multiple short discontinuous trajectories into a single long-time kinetic model but necessitates a configurational coarse-graining of the phase space that entails a loss of spatial and temporal resolution and an exponential increase in complexity for multimolecular systems. Latent space simulators (LSS) present an alternative formalism that employs a dynamical, as opposed to configurational, coarse graining comprising three back-to-back learning problems to (i) identify the molecular system's slowest dynamical processes, (ii) propagate the microscopic system dynamics within this slow subspace, and (iii) generatively reconstruct the trajectory of the system within the molecular phase space.

Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders.

Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulate disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition.

Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry.

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process.

Antibacterial and anatomical defenses in an oil contaminated, vulnerable seaduck.

Oil spills have killed thousands of birds during the last 100 years, but nonlethal effects of oil spills on birds remain poorly studied. We measured phenotype characters in 819 eiders (279 whole birds and 540 wings) of which 13.6% were oiled.

Economic and environmental assessment of bacterial poly(3-hydroxybutyrate) production from the organic fraction of municipal solid waste.

The management of municipal solid waste is a major logistic and environmental problem worldwide. Nonetheless, the organic fraction of municipal solid waste (OFMSW) is a valuable source of nutrients which can be used for a variety of purposes, according to the Circular Economy paradigm. Among the possible applications, the bioproduction of a biodegradable polyester, poly(3-hydroxybutyrate) [P(3HB)], using OFMSW as carbon platform is a promising strategy.

Giving credit to residual bioresources: From municipal solid waste hydrolysate and waste plum juice to poly (3-hydroxybutyrate).

Municipal solid waste (MSW) is massively generated all over the world. Its organic fraction (OFMSW), which represents a high percentage of MSW, mainly contains biodegradable materials, namely food waste, paper and garden waste. The social cost of OFMSW treatment and/or disposal is a serious and widespread problem, particularly in highly populated areas.

Upgrading end-of-line residues of the red seaweed to polyhydroxyalkanoates using .

Agar extraction from and red seaweed species produces hundred thousand ton of carbohydrate-rich residues annually. waste biomass obtained after agar extraction, still contained 44.2 % w/w total carbohydrates (dry-weight basis).

Upgrading the organic fraction of municipal solid waste to poly(3-hydroxybutyrate).

The organic fraction of municipal solid waste was studied as feedstock for the production of poly(3-hydroxybutyrate) (P(3HB)). To release the monosaccharides, a diluted acid pre-treatment followed by an enzymatic hydrolysis was applied. A sugar yield of 49% was achieved using a pre-treated waste and an enzyme cocktail of Pentopan 500 BG and Celluclast BG.

Accelerated molecular dynamics simulations of the octopamine receptor using GPUs: discovery of an alternate agonist-binding position.

Octopamine receptors (OARs) perform key biological functions in invertebrates, making this class of G-protein coupled receptors (GPCRs) worth considering for insecticide development. However, no crystal structures and very little research exists for OARs. Furthermore, GPCRs are large proteins, are suspended in a lipid bilayer, and are activated on the millisecond timescale, all of which make conventional molecular dynamics (MD) simulations infeasible, even if run on large supercomputers.

Determination of endocrine disrupting compounds and their metabolites in fish bile.

This work describes a new methodology for the simultaneous determination of a large variety of emerging and persistent organic compounds and some of their metabolites in fish bile samples. The target compounds were musk fragrances, alkyl phenols, hormones, pesticides, phthalate esters and bisphenol-A, all of them with a known endocrine disrupting effect. To achieve the determination these three steps were optimized: i) an enzymatic hydrolysis of the metabolites to render the unconjugated compounds; ii) the solid phase extraction of the target analytes (Plexa cartridges 200-mg); and, iii) a clean-up of the extracts (Florisil cartridges 1-g).

A comparison of weighted ensemble and Markov state model methodologies.

Computation of reaction rates and elucidation of reaction mechanisms are two of the main goals of molecular dynamics (MD) and related simulation methods. Since it is time consuming to study reaction mechanisms over long time scales using brute force MD simulations, two ensemble methods, Markov State Models (MSMs) and Weighted Ensemble (WE), have been proposed to accelerate the procedure. Both approaches require clustering of microscopic configurations into networks of "macro-states" for different purposes.

Evaluation of conformational changes in diabetes-associated mutation in insulin a chain: a molecular dynamics study.

Insulin plays a central role in the regulation of metabolism in humans. Mutations in the insulin gene can impair the folding of its precursor protein, proinsulin, and cause permanent neonatal-onset diabetes mellitus known as Mutant INS-gene induced Diabetes of Youth (MIDY) with insulin deficiency. To gain insights into the molecular basis of this diabetes-associated mutation, we perform molecular dynamics simulations in wild-type and mutant (Cys(A7) to Tyr or C(A7)Y) insulin A chain in aqueous solutions.

Characterization of the Anopheles gambiae octopamine receptor and discovery of potential agonists and antagonists using a combined computational-experimental approach.

Background: Octopamine receptors (OARs) perform key functions in the biological pathways of primarily invertebrates, making this class of G-protein coupled receptors (GPCRs) a potentially good target for insecticides. However, the lack of structural and experimental data for this insect-essential GPCR family has promoted the development of homology models that are good representations of their biological equivalents for in silico screening of small molecules.

Methods: Two Anopheles gambiae OARs were cloned, analysed and functionally characterized using a heterologous cell reporter system.

AWE-WQ: fast-forwarding molecular dynamics using the accelerated weighted ensemble.

A limitation of traditional molecular dynamics (MD) is that reaction rates are difficult to compute. This is due to the rarity of observing transitions between metastable states since high energy barriers trap the system in these states. Recently the weighted ensemble (WE) family of methods have emerged which can flexibly and efficiently sample conformational space without being trapped and allow calculation of unbiased rates.

Long Timestep Molecular Dynamics on the Graphical Processing Unit.

Molecular dynamics (MD) simulations now play a key role in many areas of theoretical chemistry, biology, physics, and materials science. In many cases, such calculations are significantly limited by the massive amount of computer time needed to perform calculations of interest. Herein, we present Long Timestep Molecular Dynamics (LTMD), a method to significantly speed MD simulations.

Identification of novel arthropod vector G protein-coupled receptors.

Background: The control of vector-borne diseases, such as malaria, dengue fever, and typhus fever is often achieved with the use of insecticides. Unfortunately, insecticide resistance is becoming common among different vector species. There are currently no chemical alternatives to these insecticides because new human-safe classes of molecules have yet to be brought to the vector-control market.

Folding Proteins at 500 ns/hour with Work Queue.

Molecular modeling is a field that traditionally has large computational costs. Until recently, most simulation techniques relied on long trajectories, which inherently have poor scalability. A new class of methods is proposed that requires only a large number of short calculations, and for which minimal communication between computer nodes is required.

Community-acquired methicillin resistant Staphylococcus aureus: a new aetiological agent of prostatic abscess.

Prostatic abscess is rare. Its potentially serious course requires a high level of clinical suspicion and prompt and effective treatment. The causative germs are usually either enterobacteria or Enterococcus.

Modeling conformational ensembles of slow functional motions in Pin1-WW.

Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging.

Multiscale dynamics of macromolecules using normal mode Langevin.

Proteins and other macromolecules have coupled dynamics over multiple time scales (from femtosecond to millisecond and beyond) that make resolving molecular dynamics challenging. We present an approach based on periodically decomposing the dynamics of a macromolecule into slow and fast modes based on a scalable coarse-grained normal mode analysis. A Langevin equation is used to propagate the slowest degrees of freedom while minimizing the nearly instantaneous degrees of freedom.

Estimation of protein and domain interactions in the switching motility system of Myxococcus xanthus.

The gram-negative myxobacterium Myxococcus xanthus is equipped with an interesting motility system that allows it to reverse direction on average every 8 minutes by switching the construction of two motility engines at the ends of this rod-shaped bacterium. While the mechanisms responsible for timing and engine construction/deconstruction are relatively well understood, there are several competing hypotheses as to how they are coupled together. In this paper we examine the evidence for protein interactions underlying these possible couplings using a novel framework consisting of a probabilistic model describing protein and domain interactions and a belief propagation inference algorithm.

A separable shadow Hamiltonian hybrid Monte Carlo method.

Hybrid Monte Carlo (HMC) is a rigorous sampling method that uses molecular dynamics (MD) as a global Monte Carlo move. The acceptance rate of HMC decays exponentially with system size. The shadow hybrid Monte Carlo (SHMC) was previously introduced to reduce this performance degradation by sampling instead from the shadow Hamiltonian defined for MD when using a symplectic integrator.