Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics ...from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to ...accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.
A complete tunability electromagnetic simulation model for the Ba0.6Sr0.4TiO3 (BST), with ɛr≈2000, and Mg2B2O6 (MBO), with ɛr≈7, composites is proposed here. The model is based on electrostatics, to ...simulate the effects of bias fields distribution in the composite varactor at the unbiased state to create the biased state for all volumetric mixture compositions. A bulk-ceramic varactor approach is chosen for the fabricated varactors. Varactors are fabricated with different volume compositions of BST and MBO, ranging from 10 to 100 vol-% of BST. Simulated results of the varactor model are then verified with the measured results of the varactor. The simulated and measured tunability shows considerable discrepancy at room temperature, which leads to Curie temperature TC investigation of the fabricated varactors. It has been observed that a shift in TC is directly proportional to the discrepancies in the simulated and measured tunability. After incorporating the TC shifts in the model, the results show close proximity between measured and TC-shifted simulated tunabilities with differences being reduced from around 32% to 2% for 80 vol-% BST varactor.
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•Electromagnetic modeling of tunability of BST-MBO composites.•Substitution effect and its relation with Curie temperature (TC) shift.•Incorporate TC-shift effect with electromagnetic simulation environment.
The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the ...majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-identified point mutations, achieving a root mean square error in binding free energy changes of
kcal/mol (95% confidence interval) and correctly classifying mutations as resistant or susceptible with
accuracy. Since these calculations are fast on modern GPUs, this benchmark establishes the potential for physical modeling to collaboratively support the rapid assessment and anticipation of the potential for patient mutations to affect drug potency in clinical applications.
Quasiparticle interference imaging (QPI) offers insight into the band structure of quantum materials from the Fourier transform of local density of states (LDOS) maps. Their acquisition with a ...scanning tunneling microscope is traditionally tedious due to the large number of required measurements that may take several days to complete. The recent demonstration of sparse sampling for QPI imaging showed how the effective measurement time could be fundamentally reduced by only sampling a small and random subset of the total LDOS. However, the amount of required sub-sampling to faithfully recover the QPI image remained a recurring question. Here we introduce an adaptive sparse sampling (ASS) approach in which we gradually accumulate sparsely sampled LDOS measurements until a desired quality level is achieved via compressive sensing recovery. The iteratively measured random subset of the LDOS can be interleaved with regular topographic images that are used for image registry and drift correction. These reference topographies also allow to resume interrupted measurements to further improve the QPI quality. Our ASS approach is a convenient extension to quasiparticle interference imaging that should remove further hesitation in the implementation of sparse sampling mapping schemes.
• Accumulative sampling for unknown degree of sparsity
• Controllably interrupt and resume QPI measurements
• Scattering wave conserving background subtractions
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Most organisms must cope with temperature changes. This involves genes and gene networks both as subjects and agents of cellular protection, creating difficulties in understanding. Here, we study how ...heating and cooling affect expression of single genes and synthetic gene circuits in Saccharomyces cerevisiae. We discovered that nonoptimal temperatures induce a cell fate choice between stress resistance and growth arrest. This creates dramatic gene expression bimodality in isogenic cell populations, as arrest abolishes gene expression. Multiscale models incorporating population dynamics, temperature-dependent growth rates, and Arrhenius scaling of reaction rates captured the effects of cooling, but not those of heating in resistant cells. Molecular-dynamics simulations revealed how heating alters the conformational dynamics of the TetR repressor, fully explaining the experimental observations. Overall, nonoptimal temperatures induce a cell fate decision and corrupt gene and gene network function in computationally predictable ways, which may aid future applications of engineered microbes in nonstandard temperatures.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved variants with substitutions in the spike receptor-binding domain (RBD) that affect its affinity for angiotensin-converting ...enzyme 2 (ACE2) receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites-a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single-amino acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently Asn
→Tyr (N501Y), cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change-for example, enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.
Building on the substantial progress that has been made in using free energy perturbation (FEP) methods to predict the relative binding affinities of small molecule ligands to proteins, we have ...previously shown that results of similar quality can be obtained in predicting the effect of mutations on the binding affinity of protein–protein complexes. However, these results were restricted to mutations which did not change the net charge of the side chains due to known difficulties with modeling perturbations involving a change in charge in FEP. Various methods have been proposed to address this problem. Here we apply the co-alchemical water approach to study the efficacy of FEP calculations of charge changing mutations at the protein–protein interface for the antibody–gp120 system investigated previously and three additional complexes. We achieve an overall root mean square error of 1.2 kcal/mol on a set of 106 cases involving a change in net charge selected by a simple suitability filter using side-chain predictions and solvent accessible surface area to be relevant to a biologic optimization project. Reasonable, although less precise, results are also obtained for the 44 more challenging mutations that involve buried residues, which may in some cases require substantial reorganization of the local protein structure, which can extend beyond the scope of a typical FEP simulation. We believe that the proposed prediction protocol will be of sufficient efficiency and accuracy to guide protein engineering projects for which optimization and/or maintenance of a high degree of binding affinity is a key objective.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We ...show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development.
A finite element method (FEM)-based simulation approach to predict the tunability in composite materials was developed and tested with analytical data. These tests showed good prediction capabilities ...of the simulation for the test data. The simulation model was then used to predict the tunability of a network-structured composite, where the dielectric phase formed clusters in a paraelectric network. This was achieved by simulating a reciprocal core-shell unit cell of said network. The simulation showed a high tunability for this network model, exceeding the tunability of the analytically evaluated layered, columnar, and particulate model. The simulation results were experimentally verified with a Ba
Sr
TiO
/Mg
B
O
(BST/MBO) composite, where core-shell granulates were made with a two-step granulation process. These structured samples showed higher tunability and dielectric loss than the unstructured samples made for comparison. Overall, the structured samples showed higher tunability to loss ratios, indicating their potential for use in tunable radio frequency applications, since they may combine high performance with little energy loss.
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