7,231 research outputs found
Energy Landscape and Global Optimization for a Frustrated Model Protein
The three-color (BLN) 69-residue model protein was designed to exhibit frustrated folding. We investigate the energy landscape of this protein using disconnectivity graphs and compare it to a Go model, which is designed to reduce the frustration by removing all non-native attractive interactions. Finding the global minimum on a frustrated energy landscape is a good test of global optimization techniques, and we present calculations evaluating the performance of basin-hopping and genetic algorithms for this system.Comparisons are made with the widely studied 46-residue BLN protein.We show that the energy landscape of the 69-residue BLN protein contains several deep funnels, each of which corresponds to a different β-barrel structure
First-principles molecular structure search with a genetic algorithm
The identification of low-energy conformers for a given molecule is a
fundamental problem in computational chemistry and cheminformatics. We assess
here a conformer search that employs a genetic algorithm for sampling the
low-energy segment of the conformation space of molecules. The algorithm is
designed to work with first-principles methods, facilitated by the
incorporation of local optimization and blacklisting conformers to prevent
repeated evaluations of very similar solutions. The aim of the search is not
only to find the global minimum, but to predict all conformers within an energy
window above the global minimum. The performance of the search strategy is: (i)
evaluated for a reference data set extracted from a database with amino acid
dipeptide conformers obtained by an extensive combined force field and
first-principles search and (ii) compared to the performance of a systematic
search and a random conformer generator for the example of a drug-like ligand
with 43 atoms, 8 rotatable bonds and 1 cis/trans bond
Protein Docking by the Underestimation of Free Energy Funnels in the Space of Encounter Complexes
Similarly to protein folding, the association of two proteins is driven
by a free energy funnel, determined by favorable interactions in some neighborhood of the
native state. We describe a docking method based on stochastic global minimization of
funnel-shaped energy functions in the space of rigid body motions (SE(3)) while accounting
for flexibility of the interface side chains. The method, called semi-definite
programming-based underestimation (SDU), employs a general quadratic function to
underestimate a set of local energy minima and uses the resulting underestimator to bias
further sampling. While SDU effectively minimizes functions with funnel-shaped basins, its
application to docking in the rotational and translational space SE(3) is not
straightforward due to the geometry of that space. We introduce a strategy that uses
separate independent variables for side-chain optimization, center-to-center distance of the
two proteins, and five angular descriptors of the relative orientations of the molecules.
The removal of the center-to-center distance turns out to vastly improve the efficiency of
the search, because the five-dimensional space now exhibits a well-behaved energy surface
suitable for underestimation. This algorithm explores the free energy surface spanned by
encounter complexes that correspond to local free energy minima and shows similarity to the
model of macromolecular association that proceeds through a series of collisions. Results
for standard protein docking benchmarks establish that in this space the free energy
landscape is a funnel in a reasonably broad neighborhood of the native state and that the
SDU strategy can generate docking predictions with less than 5 � ligand interface Ca
root-mean-square deviation while achieving an approximately 20-fold efficiency gain compared
to Monte Carlo methods
Paradigms for computational nucleic acid design
The design of DNA and RNA sequences is critical for many endeavors, from DNA nanotechnology, to PCR‐based applications, to DNA hybridization arrays. Results in the literature rely on a wide variety of design criteria adapted to the particular requirements of each application. Using an extensively studied thermodynamic model, we perform a detailed study of several criteria for designing sequences intended to adopt a target secondary structure. We conclude that superior design methods should explicitly implement both a positive design paradigm (optimize affinity for the target structure) and a negative design paradigm (optimize specificity for the target structure). The commonly used approaches of sequence symmetry minimization and minimum free‐energy satisfaction primarily implement negative design and can be strengthened by introducing a positive design component. Surprisingly, our findings hold for a wide range of secondary structures and are robust to modest perturbation of the thermodynamic parameters used for evaluating sequence quality, suggesting the feasibility and ongoing utility of a unified approach to nucleic acid design as parameter sets are refined further. Finally, we observe that designing for thermodynamic stability does not determine folding kinetics, emphasizing the opportunity for extending design criteria to target kinetic features of the energy landscape
Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-d-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors
Following our recent study of N-(β-D-glucopyranosyl)-oxadiazole-carboxamides (Polyák et al., Biorg. Med. Chem. 2013, 21, 5738) revealed as moderate inhibitors of glycogen phosphorylase (GP), in silico docking calculations using Glide have been performed on N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides with different aryl substituents predicting more favorable binding at GP. The ligands were subsequently synthesized in moderate yields using N-(2,3,4,6-terta-O-acetyl-β-D-glucopyranosyl)-tetrazole-5-carboxamide as starting material. Kinetics experiments against rabbit muscle glycogen phosphorylase b (RMGPb) revealed the ligands to be low µM GP inhibitors; the phenyl analogue (Ki = 1 µM) is one of the most potent N-(β-D-glucopyranosyl)-heteroaryl-carboxamide-type inhibitors of the GP catalytic site discovered to date. Based on QM and QM/MM calculations, the potency of the ligands is predicted to arise from favorable intra- and intermolecular hydrogen bonds formed by the most stable solution phase tautomeric (t2) state of the 1,2,4-triazole in a conformationally dynamic system. ADMET property predictions revealed the compounds to have promising pharmacokinetic properties without any toxicity. This study highlights the benefits of a computationally lead approach to GP inhibitor design
The Solution Structures of Two Human IgG1 Antibodies Show Conformational Stability and Accommodate Their C1q and FcγR Ligands.
The human IgG1 antibody subclass shows distinct properties compared with the IgG2, IgG3, and IgG4 subclasses and is the most exploited subclass in therapeutic antibodies. It is the most abundant subclass, has a half-life as long as that of IgG2 and IgG4, binds the FcγR receptor, and activates complement. There is limited structural information on full-length human IgG1 because of the challenges of crystallization. To rectify this, we have studied the solution structures of two human IgG1 6a and 19a monoclonal antibodies in different buffers at different temperatures. Analytical ultracentrifugation showed that both antibodies were predominantly monomeric, with sedimentation coefficients s20,w (0) of 6.3-6.4 S. Only a minor dimer peak was observed, and the amount was not dependent on buffer conditions. Solution scattering showed that the x-ray radius of gyration Rg increased with salt concentration, whereas the neutron Rg values remained unchanged with temperature. The x-ray and neutron distance distribution curves P(r) revealed two peaks, M1 and M2, whose positions were unchanged in different buffers to indicate conformational stability. Constrained atomistic scattering modeling revealed predominantly asymmetric solution structures for both antibodies with extended hinge structures. Both structures were similar to the only known crystal structure of full-length human IgG1. The Fab conformations in both structures were suitably positioned to permit the Fc region to bind readily to its FcγR and C1q ligands without steric clashes, unlike human IgG4. Our molecular models for human IgG1 explain its immune activities, and we discuss its stability and function for therapeutic applications
Impact of vibrational entropy on the stability of unsolvated peptide helices with increasing length
Helices are a key folding motif in protein structure. The question which
factors determine helix stability for a given polypeptide or protein is an
ongoing challenge. Here we use van der Waals corrected density-functional
theory to address a part of this question in a bottom-up approach. We show how
intrinsic helical structure is stabilized with length and temperature for a
series of experimentally well studied unsolvated alanine based polypeptides,
Ac-Alan-LysH+. By exploring extensively the conformational space of these
molecules, we find that helices emerge as the preferred structure in the length
range n=4-8 not just due to enthalpic factors (hydrogen bonds and their
cooperativity, van der Waals dispersion interactions, electrostatics), but
importantly also by a vibrational entropic stabilization over competing
conformers at room temperature. The stabilization is shown to be due to softer
low-frequency vibrational modes in helical conformers than in more compact
ones. This observation is corroborated by including anharmonic effects
explicitly through \emph{ab initio} molecular dynamics, and generalized by
testing different terminations and considering larger helical peptide models
Exploration of Reaction Pathways and Chemical Transformation Networks
For the investigation of chemical reaction networks, the identification of
all relevant intermediates and elementary reactions is mandatory. Many
algorithmic approaches exist that perform explorations efficiently and
automatedly. These approaches differ in their application range, the level of
completeness of the exploration, as well as the amount of heuristics and human
intervention required. Here, we describe and compare the different approaches
based on these criteria. Future directions leveraging the strengths of chemical
heuristics, human interaction, and physical rigor are discussed.Comment: 48 pages, 4 figure
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