Future of fundamental discovery in US biomedical research

Levitt, Michael; Levitt, Jonathan M.

doi:10.1073/pnas.1609996114

Cited by 72 publications

(65 citation statements)

References 50 publications

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“…Based on experimental 43 and theoretical 44 evidence, it appears that linear B-DNA free in solution is most stable with about 10.5 base pairs per turn rather than 10 as observed in the solid state, whereas superhelical DNA in chromatin is most stable with about 10 base pairs per turn. B-DNA is thus associated with an average twist angle of 360/10.5 = 34.31 while nucleosomal DNA corresponds to an average twist angle of 361.…”

Section: B Base Pair Dimers Of Nucleobasesmentioning

confidence: 99%

Predicting near-UV electronic circular dichroism in nucleosomal DNA by means of DFT response theory

Norman

Parello

Polavarapu

et al. 2015

Phys. Chem. Chem. Phys.

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It is demonstrated that time-dependent density functional theory (DFT) calculations can accurately predict changes in near-UV electronic circular dichroism (ECD) spectra of DNA as the structure is altered from the linear (free) B-DNA form to the supercoiled N-DNA form found in nucleosome core particles. At the DFT/B3LYP level of theory, the ECD signal response is reduced by a factor of 6.7 in going from the B-DNA to the N-DNA form, and it is illustrated how more than 90% of the individual base-pair dimers contribute to this strong hypochromic effect. Of the several inter-base pair parameters, an increase in twist angles is identified as to strongly contribute to a reduced ellipticity. The present work provides first evidence that first-principles calculations can elucidate changes in DNA dichroism due to the supramolecular organization of the nucleoprotein particle and associates these changes with the local structural features of nucleosomal DNA.

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Section: B Base Pair Dimers Of Nucleobasesmentioning

confidence: 99%

Predicting near-UV electronic circular dichroism in nucleosomal DNA by means of DFT response theory

Norman

Parello

Polavarapu

et al. 2015

Phys. Chem. Chem. Phys.

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“…The number of deposited structures in the PDB has been increasing over the last 15 years, totalizing today more than 140 000 entries. This surge has been fueled by structural genomics initiatives, aimed at developing representative structures of different protein families. But still there is a growing gap between the number of annotated sequences and 3D experimentally solved structures.…”

Section: Methodological Developments In Docking‐based Drug Lead Discomentioning

confidence: 99%

Computational chemistry in drug lead discovery and design

Cavasotto

Aucar

Adler

2018

Int J of Quantum Chemistry

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The main contributions of our group during the last 15 years developing and using biomolecular simulation tools in drug lead discovery and design, in close collaboration with experimental researchers, are presented. Special emphasis has been given to methodological improvements in the following areas: (1) target homology modeling incorporating knowledge about known ligands to accurately characterize the binding site; (2) designing alternative strategies to account for protein flexibility in high‐throughput docking; (3) development of stochastic‐ and normal‐mode‐based methods to de novo design structurally diverse protein conformers; (4) development and validation of quantum mechanical semi‐empirical linear‐scaling calculations to correctly estimate ligand binding free energy. Several successful cases of computer‐aided drug discovery are also presented, especially our recent work on viral targets.

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“…do not appear to be less creative or capable (5). Current NIH paylines are well below those seen at the time of the NIH doubling, yet follow-up analyses have suggested essentially equivalent productivity of NIH grants that received peer review scores near the top of the fundable range during those morefavorable times (13,14).…”

Section: Funding Sourcesmentioning

confidence: 98%