David W. Kastner
(He/Him)
Boston
As seen in:
Nature,
Wiley Online Library,
ACS Publications,
Royal Society of Chemistry,
BioRxiv,
Cell Press,
The Journal of Biological Chemistry
Covers:
protein engineering, bioengineering, molecular dynamics, quantum mechanics
MIT Bioengineering Ph.D. student and artist studying high-valent metalloenzymes. illustratedatom.com
Articles by David W. Kastner
QuantumPDB: A Workflow for High-Throughput Quantum Cluster Model Generation from Protein Structures Click to copy article link Article link copied!
1. Introduction Click to copy section linkSection link copied! Enzymes catalyze challenging chemical transformations with high efficiency and selectivity under physiological conditions. (1−3) Their remarkable activity results from electronic and electrostatic properties such as polarization, (4,5) charge transfer, (6−8) local electric fields, (9−16) as well as precise substrate positioning (17−19) and conformational dynamics.
pyEF: A Python Framework for QM and QM/MM Atom-Wise Electric Field Analysis Click to copy article link Article link copied!
1. Introduction Click to copy section linkSection link copied! Electrostatic preorganization is increasingly recognized as a central driving force in catalytic reactions. Warshel first proposed that strong electric fields exist within enzyme active sites and play a crucial role in enzymatic rate enhancement.
The energetic landscape of CH-π interactions in protein-carbohydrate binding
The energetic landscape of CH–π interactions in protein–carbohydrate binding† CH–π interactions between carbohydrates and aromatic amino acids play an essential role in biological systems that span all domains of life. Quantifying the strength and importance of these CH–π interactions is challenging because these interactions involve several atoms and can exist in many distinct orientations.
Tracing the stepwise Darwinian evolution of a plant halogenase
Abstract Halogenation chemistry is rare in plant metabolism, with the chloroalkaloid acutumine produced by Menispermaceae species being the only well characterized example, involving a specialized dechloroacutumine halogenase (DAH) from the iron(II)- and 2-oxoglutarate-dependent dioxygenase (2ODD) superfamily.
Mechanistic basis for the emergence of EPS1 as a catalyst in salicylic acid biosynthesis of Brassicaceae - Nature Communications
Abstract Salicylic acid (SA) production in Brassicaceae plants is uniquely accelerated from isochorismate by EPS1, a newly identified enzyme in the BAHD acyltransferase family. We present crystal structures of EPS1 from Arabidopsis thaliana in both its apo and substrate-analog-bound forms. Integrating microsecond-scale molecular dynamics simulations with quantum mechanical cluster modeling, we propose a pericyclic rearrangement lyase mechanism for EPS1.
Enzymatic synthesis of azide by a promiscuous N-nitrosylase - Nature Chemistry
Abstract Azides are energy-rich compounds with diverse representation in a broad range of scientific disciplines, including material science, synthetic chemistry, pharmaceutical science and chemical biology. Despite ubiquitous usage of the azido group, the underlying biosynthetic pathways for its formation remain largely unknown. Here we report the characterization of an enzymatic route for de novo azide construction.
Protein3D: Enabling analysis and extraction of metal‐containing sites from the Protein Data Bank with molSimplify
1 INTRODUCTION Metalloenzymes make up nearly 40% of all enzymes1, 2 and catalyze some of nature's most challenging reactions such as the reduction of nitrogen gas to ammonia,3 splitting of water,4 and the activation of CH bonds in rather inert species with high selectivity.5, 6 Computation plays a key role in assigning intermediates7, 8 in metalloenzyme catalytic cycles, probing the electronic structure of metallocofactors,9-11 and aiding in crystallographic refinement of metal centers in...
Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY - Nature Communications
Abstract Plants contain rapidly evolving specialized enzymes that support the biosynthesis of functionally diverse natural products. In coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered to accelerate coumarin formation as the only known BAHD enzyme to catalyze an intramolecular acyl transfer reaction. Here we investigate the structural and mechanistic basis for COSY’s coumarin synthase activity.
Probing the Mechanism of Isonitrile Formation by a Non-Heme Iron(II)-Dependent Oxidase/Decarboxylase
The isonitrile moiety is an electron-rich functionality that decorates various bioactive natural products isolated from diverse kingdoms of life. Isonitrile biosynthesis was restricted for over a decade to isonitrile synthases, a family of enzymes catalyzing a condensation reaction between l-Trp/l-Tyr and ribulose-5-phosphate. The discovery of ScoE, a non-heme iron(II) and α-ketoglutarate-dependent dioxygenase, demonstrated an alternative pathway employed by nature for isonitrile installation.
Synthesis and evaluation of potent yaku'amide A analogs
Synthesis and evaluation of potent yaku'amide A analogs† Concordia C. L. Lo,a Daniel Joaquin,a Diego A. Moyá, a Alexander Ramos,a David W. Kastner, a Stephen M. White,a Blake L. Christensen, a Joseph G. Naglich,b William J. Degnenc and Steven L.
ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer
Rachelle R. Olsen1, Abbie S. Ireland1, David W. Kastner1, Sarah M. Groves2, Kyle B. Spainhower1, Karine Pozo3, Demetra P. Kelenis3, Christopher P. Whitney1, Matthew R. Guthrie1, Sarah J. Wait1, Danny Soltero1, Benjamin L. Witt4,5, Vito Quaranta2, Jane E. Johnson3,6 and Trudy G.
Humanin induces conformational changes in the apoptosis regulator BAX and sequesters it into fibers, preventing mitochondrial outer-membrane permeabilization
Daniel L. Morris‡, David W. Kastner‡, Sabrina Johnson‡, Marie-Paule Strub‡,§, Yi He‡,§, Christopher K. E.
Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides
A comparative study of the impact of small, medium-sized, and bulky α,β-dehydroamino acids (ΔAAs) on the structure and stability of Balaram’s incipient 310-helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a–c that maintained the 310-helical shape of 1. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a–c that preferred a β-sheet-like conformation.
Humanin induces conformational changes in the apoptosis regulator BAX and sequesters it into fibers, preventing mitochondrial outer-membrane permeabilization
Daniel L Morris1, David W Kastner1, Sabrina Johnson1, Marie-Paule Strub2, Yi He1, Christopher K.E. Bleck3, Duck-Yeon Lee4 and Nico Tjandra1* 1NHLBI, National Institutes of Health, United States 2National Institutes of Health 3NHLBI, NIH, United States 4NHLBI ↵* Corresponding author; email: tjandran{at}nhlbi.nih.gov Author contributions: D.L.M., D.W.K., and S.J. formal analysis; D.L.M. validation; D.L.M., D.W.K., S.J., M.-P.S., Y.H., C.K.B., and D.-Y.L. investigation; D.L.M., D.W.K., and S.J....
“The Ultimate Triumph of Truth”
Just as with Brigham Young, Leonardo da Vinci’s ultimate allegiance wasn’t to a single discipline but rather to the “triumph of truth.” No individual or perspective is the owner of truth; truth is as widespread and diverse as those who search for it. Good morning, Elder Kearon, President Worthen, those from the university administration, members of the board of trustees, faculty, honored guests, and, of course—the reason why we are all here—the class of 2019.
"Computational Modelling of Peptides Containing Non-Standard Amino Acid" by David W. Kastner
Department Physiology and Developmental Biology Defense Date 2019-03-07 Publication Date 2019-03-13 First Faculty Advisor Steven Castle First Faculty Reader David Busath Honors Coordinator Merritt Andrus Keywords peptides, molecular dynamics, quantum mechanics, nmr, dehydroamino acids, anticancer Abstract Peptides represent a class of abundant and potent pharmaceutic compounds. Despite their appeal, the design, synthesis, and engineering of biologically relevant peptides remain a challenge.
"Progress Toward Synthetically Simplified Natural Anticancer Peptide" by David W. Kastner and Steven L. Castle
Yaku’amide A was isolated in late 2010 from the deep-sea sponge Ceratopsion sp. and exhibits potent inhibitory activity against 39 human cancer cell lines via a potentially novel mode of action. However, the total synthesis requires many steps and produces low yields. In this study, we determined two simpler YA analogues that may retain its anticancer properties and can be synthesized in larger quantities. The analogues replace dehydroisoleucine with either dehydroethylnorvaline or dehydrovaline.
Bulky Dehydroamino Acids Enhance Proteolytic Stability and Folding in β-Hairpin Peptides
The bulky dehydroamino acids dehydrovaline (ΔVal) and dehydroethylnorvaline (ΔEnv) can be inserted into the turn regions of β-hairpin peptides without altering their secondary structures. These residues increase proteolytic stability, with ΔVal at the (i + 1) position having the most substantial impact. Additionally, a bulky dehydroamino acid can be paired with a d-amino acid (i.e., d-Pro) to synergistically enhance resistance to proteolysis.
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