This Week in PNAS
BIOCHEMISTRY
Previous simulation studies have suggested that structural dynamics and protein motion play an important role in enzyme catalysis, but these results are difficult to verify experimentally. R. August Estabrook et al. have developed a predictive approach to guide the direct experimental testing of how enzyme dynamics impact catalysis. Their method highlights specific amino acid pairs likely to be essential for catalysis by identifying those that show both dynamic and evolutionary couplings. The authors combined two analytical methods, each of which measures a type of covariation between amino acid positions. Molecular dynamics simulations reveal protein regions with correlated motions, while statistical coevolution analysis finds protein segments that are highly coevolved or coupled. The authors demonstrated their approach on the DNA methyltranferase M.HhaI and found that the coevolved amino acid residues of M.HhaI with highly correlated motions in the same direction (in terms of backbone α-carbon motion) were within van der Waals contact. These interactions are believed to be critical structural elements for maintaining enzymatic functions. Coevolved residues moving in opposite directions (anticorrelated motion) were found to lie on opposing sides of the enzyme active site and may mediate active-site compressions.
Cross-correlation map of M.HhaI.
“Statistical coevolution analysis and molecular dynamics: Identification of amino acid pairs essential for catalysis” by R. August Estabrook, Jia Luo, Matthew M. Purdy, Vyas Sharma, Paul Weakliem, Thomas C. Bruice, and Norbert O. Reich (see pages 994–999)
EVOLUTION
The most common strain of laboratory yeast is evolving faster than its wild cousins, biologists report. Zhenglong Gu et al. used the maximum likelihood method to make genome-wide comparisons of the evolutionary rates of the common laboratory strain (S288c) and a wild strain (YJM789) of Saccharomyces cerevisiae. The overall evolutionary rate was ≈15% higher in the laboratory strain. Across the genome, the authors found that the laboratory strain had higher rates of synonymous substitutions in genes with strong codon usage bias. Nonsynonymous substitutions appeared more frequently in every type of gene but were also enriched in genes under stronger negative selection. The laboratory strain also had more genes that have adaptively evolved. According to the authors, experimental and possible industrial manipulation, frequent population bottlenecks, and a lack of selection pressure in the laboratory environment could all contribute to the increased evolutionary rate. The discovery implies that researchers should use caution when drawing broad, species-wide conclusions based on strains that have been domesticated and cultivated outside their normal environments.
“Elevated evolutionary rates in the laboratory strain of Saccharomyces cerevisiae” by Zhenglong Gu, Lior David, Dmitri Petrov, Ted Jones, Ronald W. Davis, and Lars M. Steinmetz (see pages 1092–1097)
NEUROSCIENCE
The way the brain processes speech sounds is determined by visual cues, suggesting that the brain analyzes speech by synthesizing a variety of inputs. When a visual and an auditory stimulus are presented simultaneously, each affects the perception of the other. For instance, the perception of auditory speech is enhanced when the listener sees the speaker's facial articulations. However, how the brain integrates these signals is not well understood. Virginie van Wassenhove et al. conducted combined psychophysical and electroencephalography experiments in 26 normal, healthy subjects to determine how speech and visual cues are processed in real time. The authors found that visual speech, measured as facial articulations while speaking, speeds up the cortical processing of auditory signals within 100 ms of signal onset. The presentation of a specific facial cue appears to narrow down the possible interpretations of the sound, sending the brain down a particular processing pathway. The data suggest that abstract internal representations exist inside the brain and are cued up by visual stimuli that constrain the downstream processing of speech sounds.
Auditory-visual speech.
“Visual speech speeds up the neural processing of auditory speech” by Virginie van Wassenhove, Ken W. Grant, and David Poeppel (see pages 1181–1186)
NEUROSCIENCE
Despite its proposed effects on axonal regeneration, the Nogo receptor (NgR) may not be the universal missing link that mediates axon regeneration failure. Three myelin-associated proteins—Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp)—are implicated in inhibiting the regeneration of damaged axons in the adult mammalian nervous system. Since NgR binds to these proteins and complexes with the neurotrophin receptor (p75NTR), scientists have speculated that NgR might act as a universal link to mediate the inhibitory effects of these proteins. However, Binhai Zheng et al. demonstrate that NgR is unlikely to be a single central mediator of regeneration failure. In neurons taken from mice lacking NgR, exposure to myelin or to a Nogo peptide inhibited outgrowth of specific axonal classes to the same extent as in wild-type neurons. Additionally, NgR-deficient mice showed no evidence of improved corticospinal tract regeneration. In contrast, confirming previous studies, the authors found that neurons from p75NTR-deficient mice showed less inhibition by myelin inhibitors in vitro but still no improvement in corticospinal tract regeneration. These findings provide both in vivo and in vitro evidence that NgR, in the cell types tested, cannot by itself account for myelin-induced regeneration failure. The identity of the receptor(s) that mediate myelin inhibition in those neurons remains to be defined.
Axon regeneration in Nogo-deficient mice.
“Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo” by Binhai Zheng, Jasvinder Atwal, Carole Ho, Lauren Case, Xiao-lin He, K. Christopher Garcia, Oswald Steward, and Marc Tessier-Lavigne (see pages 1205–1210)
ECONOMIC SCIENCES
A mathematical modeling of the economics of intellectual property suggests that patents and copyrights should be eliminated. According to a theory developed by Michele Boldrin and David Levine, government-granted monopolies are not the best incentives for innovation. The authors apply economic theory to the trade of ideas, arguing that ideas would benefit from free trade just as other, more tangible, items have. They predicate their argument on limited capacity, i.e., the concept that the ability to produce copies of an idea is limited after its discovery. The authors mathematically argue that innovators can earn substantial profits without patent protection, whereas intellectual monopolies can cause rent seeking, overpricing, undersupplying, and discouragement of future innovation. In particular, the authors show that, as the number of old ideas needed to produce a new idea increases, innovation stalls under monopoly. The authors' model recognizes that producing the first copy of an idea entails an indivisibility. Because indivisibilities are less relevant in large markets, the authors seek to find the optimal level of intellectual protection as a function of market size.
“The economics of ideas and intellectual property” by Michele Boldrin and David K. Levine (see pages 1252–1256)
