William F. DeGrado

Bio: William F. DeGrado is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Protein structure & Transmembrane domain. The author has an hindex of 110, co-authored 599 publications receiving 43508 citations. Previous affiliations of William F. DeGrado include Imperial College London & Iowa State University.

A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids

Abstract: Amino acids have distinct conformational preferences that influence the stabilities of protein secondary and tertiary structures. The relative thermodynamic stabilities of each of the 20 commonly occurring amino acids in the alpha-helical versus random coil states have been determined through the design of a peptide that forms a noncovalent alpha-helical dimer, which is in equilibrium with a randomly coiled monomeric state. The alpha helices in the dimer contain a single solvent-exposed site that is surrounded by small, neutral amino acid side chains. Each of the commonly occurring amino acids was substituted into this guest site, and the resulting equilibrium constants for the monomer-dimer equilibrium were determined to provide a list of free energy difference (delta delta G degree) values.

Foldamers as versatile frameworks for the design and evolution of function

Abstract: Foldamers are sequence-specific oligomers akin to peptides, proteins and oligonucleotides that fold into well-defined three-dimensional structures They offer the chemical biologist a broad pallet of building blocks for the construction of molecules that test and extend our understanding of protein folding and function Foldamers also provide templates for presenting complex arrays of functional groups in virtually unlimited geometrical patterns, thereby presenting attractive opportunities for the design of molecules that bind in a sequence- and structure-specific manner to oligosaccharides, nucleic acids, membranes and proteins We summarize recent advances and highlight the future applications and challenges of this rapidly expanding field

Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers

Abstract: The current H1N1 strain pandemic virus is resistant to the established antiviral agents amantadine and rimantadine, which target the M2 protein, a multifunctional membrane-spanning proton channel The structure of this channel has been a subject of some controversy, since an X-ray crystal structure of part of the M2 channel showed electron density that corresponded to a single molecule of amantadine in the N-terminal half of the pore, whereas a solution NMR structure of a larger portion of the channel showed four rimantadine molecules bound to the C-terminal lipid-facing surface of the helices The matter now appears resolved with the publication of the high-resolution structure of the M2 channel in a phospholipid bilayer, determined using solid-state NMR spectroscopy This reveals two amantadine-binding sites: a high-affinity site in the N-terminal channel lumen and a low-affinity site on the C-terminal protein surface This work could be of value for the development of new anti-influenza drugs, an important goal since the 2009 seasonal virus is amantadine-sensitive but resistant to Tamiflu, raising the possibility that multiply resistant virus types might emerge in future The antiviral drugs amantadine and rimantadine target the M2 protein of influenza A virus, making an understanding of its structure important for the study of drug resistance The results of a recent crystal structure of M2 differ from those of a solution NMR structure with regards to binding of these drugs, indicating a different mechanism of inhibition in each case Here, using solid-state NMR spectroscopy, two different amantadine-binding sites are shown to exist in the phospholipid bilayers of M2 The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine1 Resistance to these drugs has compromised their effectiveness against many influenza strains, including pandemic H1N1 A recent crystal structure of M2(22–46) showed electron densities attributed to a single amantadine in the amino-terminal half of the pore2, indicating a physical occlusion mechanism for inhibition However, a solution NMR structure of M2(18–60) showed four rimantadines bound to the carboxy-terminal lipid-facing surface of the helices3, suggesting an allosteric mechanism Here we show by solid-state NMR spectroscopy that two amantadine-binding sites exist in M2 in phospholipid bilayers The high-affinity site, occupied by a single amantadine, is located in the N-terminal channel lumen, surrounded by residues mutated in amantadine-resistant viruses Quantification of the protein–amantadine distances resulted in a 03 A-resolution structure of the high-affinity binding site The second, low-affinity, site was observed on the C-terminal protein surface, but only when the drug reaches high concentrations in the bilayer The orientation and dynamics of the drug are distinct in the two sites, as shown by 2H NMR These results indicate that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses The study demonstrates the ability of solid-state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes

Fast parallel algorithms for short-range molecular dynamics

Abstract: Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Phd by thesis

Abstract: Deposits of clastic carbonate-dominated (calciclastic) sedimentary slope systems in the rock record have been identified mostly as linearly-consistent carbonate apron deposits, even though most ancient clastic carbonate slope deposits fit the submarine fan systems better. Calciclastic submarine fans are consequently rarely described and are poorly understood. Subsequently, very little is known especially in mud-dominated calciclastic submarine fan systems. Presented in this study are a sedimentological core and petrographic characterisation of samples from eleven boreholes from the Lower Carboniferous of Bowland Basin (Northwest England) that reveals a >250 m thick calciturbidite complex deposited in a calciclastic submarine fan setting. Seven facies are recognised from core and thin section characterisation and are grouped into three carbonate turbidite sequences. They include: 1) Calciturbidites, comprising mostly of highto low-density, wavy-laminated bioclast-rich facies; 2) low-density densite mudstones which are characterised by planar laminated and unlaminated muddominated facies; and 3) Calcidebrites which are muddy or hyper-concentrated debrisflow deposits occurring as poorly-sorted, chaotic, mud-supported floatstones. These