We present an approach to assess antibody CDR-H3 loops according their dynamic properties using molecular dynamics simulations. selected six antibodies in three pairs differing substantially individual promiscuity respectively specificity. For two of crystal structures are available different states maturation and used as starting for the analyses. a third pair we chose CDR sequences obtained from synthetic library predicted respective structures. all performed metadynamics simulations...

Enzymatic function and activity of proteases is closely controlled by the pH value. The protonation states titratable residues in active site react to changes value, according their pKa, thereby determine functionality enzyme. Knowledge titration behavior these crucial for development drugs targeting residues. However, experimental pKa data are scarce, since systems' size complexity make determination values inherently difficult. In this study, we use single constant MD simulations as a fast...

We analyzed pairs of protein-binding, peptide-binding and hapten-binding antibodies crystallized as complex in the absence antigen with without conformational differences upon binding complementarity-determining region (CDR)-H3 loop. Here, we introduce a molecular dynamics-based approach to capture diverse ensemble CDR-H3 loop solution. The results clearly indicate that inherently flexible indeed needs be characterized ensemble. changes all investigated follow paradigm conformation...

Solvation and hydrophobicity play a key role in variety of biological mechanisms. In substrate binding, but also structure-based drug design, the thermodynamic properties water molecules surrounding given protein are high interest. One main algorithms devised recent years to quantify is grid inhomogeneous solvation theory (GIST), which calculates these features on protein. Despite inherent advantages GIST, computational demand major drawback, as calculations for larger systems can take days...

Molecular dynamics simulations are an invaluable tool to characterize the dynamic motions of proteins in atomistic detail. However, accuracy models derived from inevitably relies on quality underlying force field. Here, we present evaluation current non-polarizable and polarizable fields (AMBER ff14SB, CHARMM 36m, GROMOS 54A7, Drude 2013) based long-standing biophysical challenge protein folding. We quantify thermodynamics kinetics β-hairpin formation using Markov state fast-folding...

Late-stage functionalization (LSF) is a powerful method to quickly generate new analogues of lead structure without resorting de novo synthesis. We have leveraged Baran Diversinates carry out late-stage functionalizations on structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, decrease reaction time, increase...

Biomolecular recognition between proteins follows complex mechanisms, the understanding of which can substantially advance drug discovery efforts. Here, we track each step binding process in atomistic detail with molecular dynamics simulations using trypsin and its inhibitor bovine pancreatic (BPTI) as a model system. We use umbrella sampling to cover range unbinding pathways. Starting from these simulations, subsequently seed classical at different stages combine them Markov state model....

A major challenge in the development of antibody biotherapeutics is their tendency to aggregate. One root cause for aggregation exposure hydrophobic surface regions solvent. Many current techniques predict relative propensity antibodies via precalculated scales hydrophobicity or single amino acids. However, those cannot describe nonadditive effects a residue's surrounding on its hydrophobicity. Therefore, they are inherently limited ability impact subtle differences molecular structure...

β-Glucosidases are enzymes with high importance for many industrial processes, catalyzing the last and limiting step of conversion lignocellulosic material into fermentable sugars biofuel production. However, β-glucosidases inhibited by concentrations product (glucose), which limits production on an scale. For this reason, structural mechanisms tolerance to inhibition have been target several studies. In study, we performed in silico experiments, such as molecular dynamics (MD) simulations,...

X-Entropy is a Python package used to calculate the entropy of given distribution, in this case, based on distribution dihedral angles. The facilitates an alignment-independent measure local protein flexibility. key feature our approach Gaussian kernel density estimation (KDE) using plug-in bandwidth selection, which fully implemented C++ backend and parallelized with OpenMP. We further provide frontend, predefined wrapper functions for classical coordinate-based calculations, 1D...

The relation of surface polarity and conformational preferences is decisive for cell permeability thus bioavailability macrocyclic drugs. Here, we employ grid inhomogeneous solvation theory (GIST) to calculate free energies a series six macrocycles in water chloroform as measure passive membrane permeability. We perform accelerated molecular dynamics simulations capture diverse structural ensemble chloroform, allowing direct profiling solvent-dependent preferences. Subsequent GIST...

Reliable information on partition coefficients plays a key role in drug development, as solubility decisively affects bioavailability. In physicochemical context, the coefficient of solute between two different solvents can be described function solvation free energies. Hence, substantial scientific efforts have been made toward accurate predictions energies various solvents. The grid inhomogeneous theory (GIST) facilitates calculation this study, we introduce an extended version GIST...

Hydration thermodynamics play a fundamental role in fields ranging from the pharmaceutical industry to environmental research. Numerous methods exist predict solvation of compounds small molecules large biomolecules. Arguably most precise are those based on molecular dynamics (MD) simulations explicit solvent. One theory that has seen increased use is inhomogeneous (IST). However, while many applications require accurate description salt-water mixtures, no implementation IST currently able...

Abstract Serine proteases of the Chymotrypsin family are structurally very similar but have different substrate preferences. This study investigates a set 9 this comprising that prefer substrates containing positively charged amino acids, negatively and uncharged acids with varying degree specificity. Here, we show differences in electrostatic preferences can be predicted reliably by molecular interaction fields employing customized GRID probes. Thus, able to directly link protease...

The equilibrium between active E and inactive E* forms of thrombin is assumed to be governed by the allosteric binding a Na+ ion. Here we use molecular dynamics simulations Markov state models sample transitions states. With these calculations are able compare thermodynamic kinetic properties depending on presence Na+. For first time, directly observe sodium-induced conformational changes in long-timescale computer simulations. Thereby, explain resulting change activity. We stabilization...

Grid Inhomogeneous Solvation Theory (GIST) has proven useful to calculate localized thermodynamic properties of water around a solute. Numerous studies have leveraged this information enhance structure-based binding predictions. We recently extended GIST toward chloroform as solvent allow the prediction passive membrane permeability. Here, we further generalize algorithm all solvents that can be modeled rigid molecules. This restriction is inherent method and already present in inhomogeneous...

For more than half a century computer simulations were developed and employed to study ensemble properties of wide variety atomic molecular systems with tremendous success. Nowadays, selection force-fields is available that describe the interactions in such systems. A key feature an adequate description electrostatic potential (ESP). Several model ESP via point charges positioned at atom centers. major shortcoming this approach, its inability anisotropies ESP, can be mitigated using...

Susceptibility to endosomal degradation is a decisive contribution protein's immunogenicity. It assumed that the processing kinetics of structured proteins are inherently linked their probability local unfolding. In this study, we quantify impact acidification on conformational stability major timothy grass pollen allergen Phl p 6. We use state art sampling approaches in combination with constant pH MD techniques profile pH-dependent unfolding events atomistic detail. Integrating our...

Abstract Summary Inter-domain orientations between immunoglobulin domains are important for the modeling and engineering of novel antibody therapeutics. Previous tools to describe these applicable only variable antibodies T-cell receptors. We present “Orientation Cylindrical Domains (OCD)” tool, which employs a transferable approach calculate inter-domain all domains. Based on reference structure, OCD tool automatically builds suitable coordinate system each domain. Through alignment,...

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