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。

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

J. Appl. Cryst.の発刊に際して

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage).

Structure validation by Calpha geometry: phi,psi and Cbeta deviation.

T e purpose of this review is to assess the nature and magnitudes of the dominant forces in protein folding. Since proteins are only marginally stable at room temperature,’ no type of molecular interaction is unimportant, and even small interactions can contribute significantly (positively or negatively) to stability (Alber, 1989a,b; Matthews, 1987a,b). However, the present review aims to identify only the largest forces that lead to the structural features of globular proteins: their extraordinary compactness, their core of nonpolar residues, and their considerable amounts of internal architecture. This review explores contributions to the free energy of folding arising from electrostatics (classical charge repulsions and ion pairing), hydrogen-bonding and van der Waals interactions, intrinsic propensities, and hydrophobic interactions. An earlier review by Kauzmann (1959) introduced the importance of hydrophobic interactions. His insights were particularly remarkable considering that he did not have the benefit of known protein structures, model studies, high-resolution calorimetry, mutational methods, or force-field or statistical mechanical results. The present review aims to provide a reassessment of the factors important for folding in light of current knowledge. Also considered here are the opposing forces, conformational entropy and electrostatics. The process of protein folding has been known for about 60 years. In 1902, Emil Fischer and Franz Hofmeister independently concluded that proteins were chains of covalently linked amino acids (Haschemeyer & Haschemeyer, 1973) but deeper understanding of protein structure and conformational change was hindered because of the difficulty in finding conditions for solubilization. Chick and Martin (191 1) were the first to discover the process of denaturation and to distinguish it from the process of aggregation. By 1925, the denaturation process was considered to be either hydrolysis of the peptide bond (Wu & Wu, 1925; Anson & Mirsky, 1925) or dehydration of the protein (Robertson, 1918). The view that protein denaturation was an unfolding process was

/pdf/dominant-forces-in-protein-folding-42bjzlldw4.pdf

Dominant forces in protein folding

A strategy for the modular construction of synthetic protein mimics based on the ability non-protein amino acids to act as stereochemical directors of polypeptide chain folding, is described. The use of alpha-aminoisobutyric acid (Aib) to construct stereochemically rigid helices has been exemplified by crystallographic and spectroscopic studies of several apolar peptides, ranging in length from seven to sixteen residues. The problem of linker design in elaborating alpha,alpha motifs has been considered. Analysis of protein crystal structure data provides a guide to choosing linking sequences. Attempts at constructing linked helical motifs using linking Gly-Pro segments have been described. The use of flexible linkers, like epsilon-aminocaproic acid has been examined and the crystallographic and solution state analysis of a linked helix motif has been presented. The use of bulky sidechain modifications on a helical scaffold, as a means of generating putative binding sites has been exemplified by a crystal structure of a peptide packed in a parallel zipper arrangement.

/pdf/the-design-and-construction-of-synthetic-protein-mimics-2qp2lm1kx1.pdf

The Design and Construction of Synthetic Protein Mimics

The Schellman motif is a widely observed, helix terminating structural motif in proteins, which is achieved by the adoption of a left-handed helical (alphaL) conformation by a C-terminus residue. The resulting hydrogen bonding pattern involves an intramolecular 6 f 1 interaction. This helix terminating motif is readily mimicked in synthetic helical peptides by placing an achiral residue at the penultimate position of the helix. The crystal structure of the heptapeptide Boc-Leu-Aib-Val-Gly-Leu-Aib-Val-OMe (1) reveals a 310-helix terminated by a Schellman motif with Aib(6) adopting an alphaL - conformation. The crystals are in the space group P21 with a = 9.958(3)A, b = 20.447-(3)A, c = 11.723 (2)A, beta = 99.74(2)°, and Z = 2. The final R1 and wR2 values are 7.2% and 18.9%, respectively, for 1731 observed reflections [I g 2U(I)]. A 6 - 1 hydrogen bond between Aib(2)CO- - - -Val(7)NH and a 5 - 2 hydrogen bond between Val(3)CO- - - -Aib(6)NH are observed. An analysis of several alphaL terminated helical peptides in crystals suggests that the medium range CialphaH- - - -Ni+3H [dRN(i,i+3)] and CialphaH- - - -Ni+4H [dRN(i,i+4)] interproton distances are indeed characteristic of the Schellman motif. NMR studies in CDCl3 establish retention of the 310-helical conformation with key NOEs demonstrating the persistence of the conformation determined in crystals. The present study demonstrates the identification of the Schellman motif in solution in a synthetic helical peptide.

/pdf/characterization-of-helix-terminating-schellman-motifs-in-1ukgmmm0n3.pdf

Characterization of Helix Terminating Schellman Motifs in Peptides. Crystal Structure and Nuclear Overhauser Effect Analysis of a Synthetic Heptapeptide Helix

A one-dimensional water wire has been characterized by X-ray diffraction in single crystals of the tripeptide Ac-Phe-Pro- Trp-OMe. Crystals in the hexagonal space group P65 reveal a central hydrophobic channel lined by aromatic residues which entraps an approximately linear array ofhydrogen bonded water molecules.The absence of any significant van der Waals contact with the channel wallssuggeststhatthedominantinteractionbetweenthe"waterwire" and"peptidenanotube"iselectrostaticinorigin.Anenergydifference of 16 kJmol 1 is estimated for the distinct orientations of the water wire dipole with respect to the macrodipole of the peptide nanotube. The structural model suggests that Grotthuss type proton conduc- tionmay,throughconstrictedhydrophobicchannels,befacilitatedby concerted, rotational reorientation of water molecules.

/pdf/entrapment-of-a-water-wire-in-a-hydrophobic-peptide-channel-3qq0odxp97.pdf

Entrapment of a water wire in a hydrophobic peptide channel with an aromatic lining.

The ideal \gamma-turn conformation in peptides is stabilized by the formation of two intramolecular hydrogen bonds. These are between the NH of residue i and the C = O of residue i + 2 (1 \rightarrow 3, $C_{11}$) and the C = O of residue i and the NH of residue i + 2 (3 \rightarrow 1, $C_7$). While this reverse-turn structural feature has been observed in proteins, unambiguous characterization of this conformation has yet to be realized in small peptides. Several examples of a single 3 \rightarrow 1 $(C_7)$ hydrogen bond have been reported in crystal structures of cyclic peptides and inferred from spectroscopic studies in apolar solvents. We wish to describe the spectroscopic characterization of a \gamma-turn conformation in a protected tripeptide, stabilized by formation of a disulfide crosslink.

http://mbu.iisc.ernet.in/%7Epbgrp/129.pdf

Stabilization of γ‐turn conformations in peptides by disulfide bridging

The Aib-(D)Ala dipeptide segment has a tendency to form both type-I'/III' and type-I/III beta-turns. The occurrence of prime turns facilitates the formation of beta-hairpin conformations, while type-I/III turns can nucleate helix formation. The octapeptide Boc-Leu-Phe-Val-Aib-(D)Ala-Leu-Phe-Val-OMe (1) has been previously shown to form a beta-hairpin in the crystalline state and in solution. The effects of sequence truncation have been examined using the model peptides Boc-Phe-Val-Aib-Xxx-Leu-Phe-NHMe (2, 6), Boc-Val-Aib-Xxx-Leu-NHMe (3, 7), and Boc-Aib-Xxx-NHMe (4, 8), where Xxx = (D)Ala, Aib. For peptides with central Aib-Aib segments, Boc-Phe-Val-Aib-Aib-Leu-Phe-NHMe (6), Boc-Val-Aib-Aib-Leu-NHMe (7), and Boc-Aib-Aib-NHMe (8) helical conformations have been established by NMR studies in both hydrogen bonding (CD(3)OH) and non-hydrogen bonding (CDCl(3)) solvents. In contrast, the corresponding hexapeptide Boc-Phe-Val-Aib-(D)Ala-Leu-Phe-Val-NHMe (2) favors helical conformations in CDCl(3) and beta-hairpin conformations in CD(3)OH. The beta-turn conformations (type-I'/III) stabilized by intramolecular 4 -> 1 hydrogen bonds are observed for the peptide Boc-Aib-(D)Ala-NHMe (4) and Boc-Aib-Aib-NIiMe (8) in crystals. The tetrapeptide Boc-Val-Aib-Aib-Leu-NHMe (7) adopts an incipient 3(10)-helical conformation stabilized by three 4 -> 1 hydrogen bonds. The peptide Boc-Val-Aib-(D)Ala-Leu-NHMe (3) adopts a novel et-turn conformation, stabilized by three intramolecular hydrogen bonds (two 4 -> 1 and one 5 -> 1). The Aib-L(D)Ala segment adopts a type-I' beta-turn conformation. The observation of an NOE between Val (1) NH HNCH(3) (5) in CD(3)OH suggests, that the solid state conformation is maintained in methanol solutions. (C) 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 744-756, 2011.

Padmanabhan Balaram

Papers

The Design and Construction of Synthetic Protein Mimics

Characterization of Helix Terminating Schellman Motifs in Peptides. Crystal Structure and Nuclear Overhauser Effect Analysis of a Synthetic Heptapeptide Helix

Entrapment of a water wire in a hydrophobic peptide channel with an aromatic lining.

Stabilization of γ‐turn conformations in peptides by disulfide bridging

Chain length effects on helix-hairpin distribution in short peptides with Aib-DAla and Aib-Aib Segments