About

Robert "Buzz" Baldwin is an Emeritus Faculty member in the Stanford Biochemistry Department. His professional biography on the Stanford webpage includes a detailed list of his students and postdoctoral fellows spanning from the 1960s through the 2000s, indicating a long-standing career in biochemistry research and mentorship. The page does not provide specific information about his research focus, background, or key contributions, but his extensive mentorship history suggests a significant role in advancing biochemistry education and research at Stanford.

Research topics

• Chemistry
• Crystallography
• Stereochemistry
• Biophysics
• Computer science

Selected publications

• Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort

  Clinical Genetics · 2019-04-30 · 25 citations

  article

  Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD-association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high-priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well-established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.

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• Author response for "Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort"

  2019-04-15

  peer-review
  PublisherDOI

• Development of a Transcriptome-Based Genome Assembly Tool and Whole Genome Sequencing for Autism Spectrum Disorders

  Brock University Digital Repository (Brock University) · 2018-05-10

  dissertationOpen access1st authorCorresponding

  This thesis consisted of two independent projects. The first involved developing a software tool that uses transcriptome data to improve genome assemblies. The second involved processing and analyzing whole genome sequencing (WGS) from the ASPIRE autism spectrum disorder (ASD) cohort.
\nThe first project produced the bioinformatics software called RDNA. This free tool was written in Perl and should be valuable for users interested in genome assembly. Comparative assessment between RDNA and the leading transcript based scaffolding software showed that RDNA can significantly improve genome assemblies while making relatively few scaffolding connection errors. RDNA also makes possible the assembly of scaffolding connections, including gap filling, using BLAST.
\nThe second project was undertaken with collaborators and involved processing and analyzing whole genome sequencing (WGS) data from the ASPIRE ASD cohort. The ASPIRE ASD cohort consisted of several hundred probands from both simplex and multiplex families. Sequencing occurred for 120 of these individuals who were selected based upon membership in two phenotype clusters (C1 and C2). These individuals had a relatively high rate of intellectual disability (ID) compared to heavily studied ASD cohorts such as the Simons Simplex Collection (SSC), indicating a significant involvement of de novo sequence variants. Analysis of rare single nucleotide variants (SNVs) and insertion/deletions (indels) identified large risk factors for severe neurodevelopmental disorders (NDDs), two of which were previously observed de novo among individuals with severe, undiagnosed NDDs. On this basis, ABCA1 was found to be a novel candidate risk gene. Gene Ontology (GO) analysis of rare loss of function and missense SNVs indicted the importance of lipid metabolic processes and synaptic signalling. Overall, the genetic variation examined by this study pertained to a modest number of cases, consistent with previous findings that ASD is a genetically heterogeneous disorder with a complex genetic architecture.

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• Clash between energy landscape theory and foldon-dependent protein folding

  Proceedings of the National Academy of Sciences · 2017-07-26 · 19 citations

  letterOpen access1st authorCorresponding

  Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.

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• A salt bridge stabilizes the helix formed by isolated C-peptide of RNase A (mechanism of protein folding/side-chain interaction/enthalpy of folding/code for helix formation)

  2016-01-01

  articleSenior author

  C-peptide, which contains the 13 NH2-terminal residues of RNase A, shows partial helix formation in water at low temperature (1?C, pH 5, 0.1 M NaCl), as judged by CD spectra; the helix is formed intramolecularly [Brown, J. E. & Klee, W. A. (1971) Biochemistry 10, 470-476]. We find that helix stability depends strongly on pH: both a protonated histidine (residue 12) and a deprotonated glutamate (residue 9 or 2 or both) are required for optimal stability. This information, together with model building, suggests that the salt bridge Glu-9* * * His-12+ stabilizes the helix. Formation ofthe helix is enthalpy driven [van't Hoff AH, -16 kcal/ mol (1 cal = 4.18 J)] and the helix is not observed above 30?C. Proton NMR data indicate that several side chains adopt specific conformations as the helix is formed. These results have two implications for the mechanism of protein folding. First, they indicate that short a-helices, stabilized by specific side-chain interactions within the helix, can be stable enough in water to function as folding intermediates. Second, they suggest that similar experiments with peptides of controlled amino acid sequence could be used to catalogue the intrahelix interactions that stabilize or destabilize a-helices in aqueous solution. These data might provide the code relating amino acid sequence to the locations of a-helices in proteins. Short a-helices, of the size range usually found in globular proteins (6-20 residues), are highly unstable in water in the absence of specific stabilizing interactions, according to data obtained with random copolymers by the host-guest technique (1). For short helices (n 99% pure) and were used to correct the CD spectra of the lactone. In NMR experiments, the resonances of the lactone and carboxylic acid forms are well resolved at low temperatures for several resonances, including the ones studied here. C-peptide concentrations were determined by the ninhydrin method (5), using leucine as a standard. To minimize interconversion between the two forms of C-peptide, the stock solutions of C-peptide lactone and carboxylic acid were kept at pH 2 and pH 10, respectively. HPLC. The lactone and carboxylic acid forms of C-peptide were analyzed in a Waters HPLC system (model 273 with a U6K injector, model 730 data module, and model 441 detector) using a reverse-phase column (Waters ,uBondapak C18) with detection at 214 nm. Separation was done isocratically at 25?C using a mobile phase of 6% isopropanol/10 mM ammonium acetate, pH 5.3. * Present address: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Ul. Rakowiecka 36, 02-532 Warsaw, Poland.

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• How the hydrophobic factor drives protein folding

  Proceedings of the National Academy of Sciences · 2016-10-17 · 102 citations

  articleOpen access1st authorCorresponding

  How hydrophobicity (HY) drives protein folding is studied. The 1971 Nozaki-Tanford method of measuring HY is modified to use gases as solutes, not crystals, and this makes the method easy to use. Alkanes are found to be much more hydrophobic than rare gases, and the two different kinds of HY are termed intrinsic (rare gases) and extrinsic (alkanes). The HY values of rare gases are proportional to solvent-accessible surface area (ASA), whereas the HY values of alkanes depend on special hydration shells. Earlier work showed that hydration shells produce the hydration energetics of alkanes. Evidence is given here that the transfer energetics of alkanes to cyclohexane [Wolfenden R, Lewis CA, Jr, Yuan Y, Carter CW, Jr (2015) Proc Natl Acad Sci USA 112(24):7484-7488] measure the release of these shells. Alkane shells are stabilized importantly by van der Waals interactions between alkane carbon and water oxygen atoms. Thus, rare gases cannot form this type of shell. The very short (approximately picoseconds) lifetime of the van der Waals interaction probably explains why NMR efforts to detect alkane hydration shells have failed. The close similarity between the sizes of the opposing energetics for forming or releasing alkane shells confirms the presence of these shells on alkanes and supports Kauzmann's 1959 mechanism of protein folding. A space-filling model is given for the hydration shells on linear alkanes. The model reproduces the n values of Jorgensen et al. [Jorgensen WL, Gao J, Ravimohan C (1985) J Phys Chem 89:3470-3473] for the number of waters in alkane hydration shells.

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• John Schellman and the birth of protein folding

  Proceedings of the National Academy of Sciences · 2015-05-07

  articleOpen access1st authorCorresponding

  Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.

  PublisherOA PDFDOI

• Dynamic hydration shell restores Kauzmann's 1959 explanation of how the hydrophobic factor drives protein folding

  Proceedings of the National Academy of Sciences · 2014-08-25 · 102 citations

  articleOpen access1st authorCorresponding

  Kauzmann's explanation of how the hydrophobic factor drives protein folding is reexamined. His explanation said that hydrocarbon hydration shells are formed, possibly of clathrate water, and they explain why hydrocarbons have uniquely low solubilities in water. His explanation was not universally accepted because of skepticism about the clathrate hydration shell. A revised version is given here in which a dynamic hydration shell is formed by van der Waals (vdw) attraction, as proposed in 1985 by Jorgensen et al. [Jorgensen WL, Gao J, Ravimohan C (1985) J Phys Chem 89:3470-3473]. The vdw hydration shell is implicit in theories of hydrophobicity that contain the vdw interaction between hydrocarbon C and water O atoms. To test the vdw shell model against the known hydration energetics of alkanes, the energetics should be based on the Ben-Naim standard state (solute transfer between fixed positions in the gas and liquid phases). Then the energetics are proportional to n, the number of water molecules correlated with an alkane by vdw attraction, given by the simulations of Jorgensen et al. The energetics show that the decrease in entropy upon hydration is the root cause of hydrophobicity; it probably results from extensive ordering of water molecules in the vdw shell. The puzzle of how hydrophobic free energy can be proportional to nonpolar surface area when the free energy is unfavorable and the only known interaction (the vdw attraction) is favorable, is resolved by finding that the unfavorable free energy is produced by the vdw shell.

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• Discussions about Proteins

  ASM Press eBooks · 2014-04-08 · 2 citations

  book-chapter1st authorCorresponding

  This chapter focuses on mother nature and the design of a regulatory enzyme. Jacques Monod was looking at a nascent science from his peculiar point of view, molecular evolution. Each new result was presented in the lecture as one tiny piece in the puzzle that Mother Nature had solved. Many scientists appreciate the Monod–Wyman–Changeux model (M–W–C model) because it is a simple, elegant, and imaginative proposal. The author feels sad that a very significant confrontation between two different approaches of molecular biology is reduced to a formal conflict between two hypothetical kinetic pathways. He thinks that what is really at stake is a triple issue. First, it is a good example of classical opposition between informative and selective theories in biology (in the M–W–C model, preexisting states are selected by small metabolites, the concentrations of which reflect the various physiological needs of the cell; according to Koshland and his collaborators, the ligand informs the protein structure and directs its conformational change). Second, they diverge on the basic unity or on the diversity of the structural solutions historically retained by evolution to solve a problem of regulation. Third, Monod’s theory is falsifiable: to refute it does not simply mean to show how significantly the real solutions differ from a model. In Monod, as a public man, the author found the basic need for creative freedom.

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• The new view of hydrophobic free energy

  FEBS Letters · 2013-01-18 · 51 citations

  reviewOpen access1st authorCorresponding

  In the new view, hydrophobic free energy is measured by the work of solute transfer of hydrocarbon gases from vapor to aqueous solution. Reasons are given for believing that older values, measured by solute transfer from a reference solvent to water, are not quantitatively correct. The hydrophobic free energy from gas-liquid transfer is the sum of two opposing quantities, the cavity work (unfavorable) and the solute-solvent interaction energy (favorable). Values of the interaction energy have been found by simulation for linear alkanes and are used here to find the cavity work, which scales linearly with molar volume, not accessible surface area. The hydrophobic free energy is the dominant factor driving folding as judged by the heat capacity change for transfer, which agrees with values for solvating hydrocarbon gases. There is an apparent conflict with earlier values of hydrophobic free energy from studies of large-to-small mutations and an explanation is given.

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Recent grants

• NIH Grant R37GM019988

  NIH · $3.2M · 1999

• NIH Grant R01GM019988

  NIH · $848k · 1988

• NIH Grant R01GM031475

  NIH · $2.2M · 1998

Frequent coauthors

• Der‐Hang Chin

  National Chung Hsing University

  41 shared

• Franc Avbelj

  National Institute of Chemistry

  40 shared

• Peter S. Kim

  Chan Zuckerberg Initiative (United States)

  38 shared

• Carol A. Rohl

  Institute of Informatics of the Slovak Academy of Sciences

  36 shared

• Eunice J. York

  Columbia University

  27 shared

• Kevin Shoemaker

  27 shared

• Robert Fairman

  26 shared

• Robert W. Woody

  Colorado State University

  25 shared

Labs

• Robert Baldwin LabPI