Self-Consistent Optimization of Excited States within Density-Functional Tight-Binding

We present an implementation of energies and gradients for the ΔDFTB method, an analogue of Δ-self-consistent-field density functional theory (ΔSCF) within density-functional tight-binding, for the lowest singlet excited state of closed-shell molecules. Benchmarks of ΔDFTB excitation energies, optimized geometries, Stokes shifts, and vibrational frequencies reveal that ΔDFTB provides a qualitatively correct description of changes in molecular geometries and vibrational frequencies due to excited-state relaxation. The accuracy of ΔDFTB Stokes shifts is comparable to that of ΔSCF-DFT, and ΔDFTB performs similarly to ΔSCF with the PBE functional for vertical excitation energies of larger chromophores where the need for efficient excited-state methods is most urgent. We provide some justification for the use of an excited-state reference density in the DFTB expansion of the electronic energy and demonstrate that ΔDFTB preserves many of the properties of its parent ΔSCF approach. This implementation fills an important gap in the extended framework of DFTB, where access to excited states has been limited to the time-dependent linear-response approach, and affords access to rapid exploration of a valuable class of excited-state potential energy surfaces

Deviation from standard dose-response curve by bnMAbs in a U87 target cell assay.

<p>(A) Representative experiment of PG16 neutralization of HIV pseudoviruses: MGRM-Chronic-B-017.c13, slope = 1.0 (red circle); MGRM-G-022.c02, slope = 1.2 (black square); MGRM-Chronic-B-006.c06, slope = 0.7 (light gray triangle)<b>;</b> and MGRM-AG-011.c15, slope = 0.4 (dark gray diamond). (B) The neutralization curve slopes were determined for data from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005110#ppat.1005110.g001" target="_blank">Fig 1A</a>. BnMAbs are ordered according to decreasing medians. The bars represent the medians and the whiskered bars represent the interquartile range. The data points are colored according to which site the bnMAb targets: high-mannose patch (magenta), CD4bs (red), V2 apex (blue), and MPER (green). The dotted line denotes a slope of 0.5. (C) The neutralization curve slope value of each bnMAb for each virus on the y-axis is plotted against the corresponding MPN for each virus-bnMAb pair on the x-axis. Spearman correlation was used for statistical analysis. The Spearman’s rank correlation coefficient was calculated at 0.745 and the P value <0.0001.</p

Maximum neutralization activity of bnMAbs in PBMC assays.

<p>(A) Each point on the graph represents the percent at which the neutralization curve plateaued for a single PBMC-grown clade B virus assayed in PBMC cells. The dotted line designates 90%. (B) Each point on the graph represents the percent at which the neutralization curve plateaued for a single molecular clone virus against the bnMAbs listed above the data points. Virus clones were produced in both 293T cells and PBMCs as indicated on the x-axis. The data points are colored according to which site the bnMAb targets: high-mannose patch (magenta), CD4bs (red), V2 apex (blue), gp41-gp120 interface (green). The bars represent the medians and the whiskered bars represent the interquartile range.</p

Maximum neutralization activity of bnMAbs in a TZM-bl target cell assay.

<p>(A) The bnMAbs are ordered from left to right according to decreasing medians of MPN. Each point on the graph represents the percent at which the neutralization curve plateaued for a single virus. The dotted line designates 90%. The bars represent the medians and the whiskered bars represent the interquartile range. The data points are colored according to which site the bnMAb targets: high-mannose patch (magenta), CD4bs (red), V2 apex (blue), and gp41 (green). (B) Percent viruses neutralized with a MPN of >65% (red), >90% (green), and >95% (blue). (C) Each point on the graph represents the percent at which the neutralization curve plateaued for a single virus against either PGT121 (magenta), PG9 (blue) or PGV04 (red). The assay system used to measure neutralization is indicated above the data points, which are filled circles for the monogram U87 assay and unfilled squares for the CAVD TZM-bl assay.</p

Maximum neutralization activity of bnMAbs in a U87 target cell assay.

<p>(A) The bnMAbs are ordered from left to right according to decreasing medians of percent maximum neutralization. Each point on the graph represents the percent at which the neutralization curve plateaued for a single virus. The percentages above the bars group bnMAb medians that have the same values. The dotted line designates 90%. The bars represent the medians and the whiskered bars represent the interquartile range. The data points are colored according to which site the bnMAb targets: high-mannose patch (magenta), CD4bs (red), V2 apex (blue), and MPER (green). (B) Percent viruses neutralized with a maximum neutralization of >95% (blue), >90% (green), and >65% (red). BnMAb groups are indicated above the figure in black and described in the text.</p

Percentage of viruses neutralized with a maximum neutralization.

<p>^a total number of viruses with IC₅₀ < 1μg/ml.</p><p>Percentage of viruses neutralized with a maximum neutralization.</p

W1_LLC_R1.fastq

V781-PG9 engineered Ramos cells after HIV C108 SOSIP enrichment followed by one round of selection using HIV WITO SOSIP. Immunoglobulin lambda light chain variable sequences from RT-PCR and amplification of cell mRNA performed using gene specific primers. TruSeq LT amplicon sequenced using 300x300 paired end reads on the Illumina MiSeq. This is read 1 (R1

W2_LLC_R2.fastq

V781-PG9 engineered Ramos cells after HIV C108 SOSIP enrichment followed by two rounds of selection using HIV WITO SOSIP. Immunoglobulin lambda light chain variable sequences from RT-PCR and amplification of cell mRNA performed using gene specific primers. TruSeq LT amplicon sequenced using 300x300 paired end reads on the Illumina MiSeq. This is read 2 (R2

W2_IgM_R2.fastq

V781-PG9 engineered Ramos cells after HIV C108 SOSIP enrichment followed by two rounds of selection using HIV WITO SOSIP. Immunoglobulin heavy chain variable sequences from RT-PCR and amplification of cell mRNA performed using gene specific primers. TruSeq LT amplicon sequenced using 300x300 paired end reads on the Illumina MiSeq. This is read 2 (R2

M2_LLC_R2.fastq

V781-PG9 engineered Ramos cells after HIV C108 SOSIP enrichment followed by two rounds of selection using HIV MGRM8 SOSIP.Immunoglobulin lambda light chain variable sequences from RT-PCR and amplification of cell mRNA performed using gene specific primers. TruSeq LT amplicon sequenced using 300x300 paired end reads on the Illumina MiSeq. This is read 2 (R2