The pioneering work of Ramachandran and colleagues emphasized the dominance of steric constraints in specifying the structure of polypeptides. The ubiquitous Ramachandran plot of backbone dihedral angles (f and c) defined the allowed regions of conformational space. These predictions were subsequently confirmed in proteins of known structure. Ramachandran and colleagues also investigated the influence of the backbone angle s on the distribution of allowed f/c combinations. The ''bridge region'' (f 0°and 220° c 40°) was predicted to be particularly sensitive to the value of s. Here we present an analysis of the distribution of f/c angles in 850 nonhomologous proteins whose structures are known to a resolution of 1.7 Å or less and sidechain Bfactor less than 30 Å 2 . We show that the distribution of f/c angles for all 87,000 residues in these proteins shows the same dependence on s as predicted by Ramachandran and colleagues. Our results are important because they make clear that steric constraints alone are sufficient to explain the backbone dihedral angle distributions observed in proteins. Contrary to recent suggestions, no additional energetic contributions, such as hydrogen bonding, need be invoked.
Significance StatementMicrobial lipid membranes protect and isolate a cell from its environment and play a crucial role in cellular bioenergetics by regulating the flow of nutrients and metabolites to reaction centers within. We demonstrate that membrane lipids change as a function of energy flux using a well-studied archaeon that thrives in acidic hot springs and observe an increase in membrane packing as energy becomes more limited. These observations are consistent with chemostat experiments utilizing a low temperature, neutral pH, marine archaeon. This strategy to regulate membrane homeostasis is common across GDGT-producing lineages, demonstrating that diverse taxa adjust membrane composition in response to chronic energy stress.
12 Significance Statement 13Microbial lipid membranes protect and isolate a cell from its environment while regulating 14 the flow of energy and nutrients to metabolic reaction centers within. We demonstrate that 15 membrane lipids change as a function of energy flux using a well-studied archaeon that 16 thrives in acidic hot springs and observe an increase in membrane packing as energy 17 becomes more limited. These observations are consistent with chemostat experiments 18 utilizing a low temperature, neutral pH, marine archaeon. This strategy appears to regulate 19 membrane homeostasis is common across GDGT-producing lineages, demonstrating that 20 diverse taxa adjust membrane composition in response to chronic energy stress. 21 Summary 22 23 Microorganisms regulate the composition of their membranes in response to environmental 24 cues. Many archaea maintain the fluidity and permeability of their membranes by adjusting 25 the number of cyclic moieties within the cores of their glycerol dibiphytanyl glycerol 26 tetraether (GDGT) lipids. Cyclized GDGTs increase membrane packing and stability, which 27 has been shown to help cells survive shifts in temperature and pH. However, the extent of 28 this cyclization also varies with growth phase and electron acceptor or donor limitation. 29 These observations indicate a relationship between energy metabolism and membrane 30 composition. Here we show that the average degree of GDGT cyclization increases with 31 Zhou et al. 2019 20190817 2 doubling time in continuous cultures of the thermoacidophile Sulfolobus acidocaldarius 32 (DSM 639). This is consistent with the behavior of a mesoneutrophile, Nitrosopumilus 33 maritimus SCM1. Together, these results demonstrate that archaeal GDGT distributions can 34 shift in response to electron donor flux and energy availability, independent of pH or 35 temperature. Paleoenvironmental reconstructions based on GDGTs thus capture the energy 36 available to microbes, which encompasses fluctuations in temperature and pH, as well as 37 electron donor and acceptor availability. The ability of Archaea to adjust membrane 38 composition and packing may be an important strategy that enables survival during episodes 39 of energy stress. 40 41
The side-chain dihedral angle distributions of all amino acids have been measured from myriad high-resolution protein crystal structures. However, we do not yet know the dominant interactions that determine these distributions. Here, we explore to what extent the defining features of the side-chain dihedral angle distributions of different amino acids can be captured by a simple physical model. We find that a hard-sphere model for a dipeptide mimetic that includes only steric interactions plus stereochemical constraints is able to recapitulate the key features of the back-bone dependent observed amino acid side-chain dihedral angle distributions of Ser, Cys, Thr, Val, Ile, Leu, Phe, Tyr, and Trp. We find that for certain amino acids, performing the calculations with the amino acid of interest in the central position of a short α-helical segment improves the match between the predicted and observed distributions. We also identify the atomic interactions that give rise to the differences between the predicted distributions for the hard-sphere model of the dipeptide and that of the α-helical segment. Finally, we point out a case where the hard-sphere plus stereochemical constraint model is insufficient to recapitulate the observed side-chain dihedral angle distribution, namely the distribution P(χ₃) for Met.
The energy functions used to predict protein structures typically include both molecular-mechanics and knowledge-based terms. In contrast, our approach is to develop robust physics- and geometry-based methods. Here, we investigate to what extent simple hard-sphere models can be used to predict side-chain conformations. The distributions of the side-chain dihedral angle χ(1) of Val and Thr in proteins of known structure show distinctive features: Val side chains predominantly adopt χ(1) = 180°, whereas Thr side chains typically adopt χ(1) = 60° and 300° (i.e., χ(1) = ±60° or g- and g(+) configurations). Several hypotheses have been proposed to explain these differences, including interresidue steric clashes and hydrogen-bonding interactions. In contrast, we show that the observed side-chain dihedral angle distributions for both Val and Thr can be explained using only local steric interactions in a dipeptide mimetic. Our results emphasize the power of simple physical approaches and their importance for future advances in protein engineering and design.
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