The hydration of amides in helices; a comprehensive picture from molecular dynamics, IR, and NMR

Walsh, Scott T. R.; Cheng, Richard P.; Wright, Wayne W.; Alonso, Darwin O. V.; Daggett, Valerie; Vanderkooi, Jane M.; DeGrado, William F.

doi:10.1110/ps.0223003

Cited by 150 publications

(197 citation statements)

References 46 publications

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“…6B, left). In these samples, the maximum shift of the low frequency ␣-helix band and its increase in intensity were consistent with the existence of packing interactions between solvated helices (67,68).…”

Section: F5 Binding To Liposomalsupporting

confidence: 74%

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Serrano

Araujo

Apellániz

et al. 2014

Journal of Biological Chemistry

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Background: HIV-1 vaccines should elicit broadly neutralizing antibodies as the gp41 "membrane-proximal external region" targeting MAb2F5. Results: NMR disclosed unprecedented 2F5 peptide-epitope structures. Although overall conformation was preserved in different adjuvants, recovered antibodies after vaccination were functionally different. Conclusion: Membrane-inserted helical oligomers may encompass effective 2F5 peptide vaccines. Significance: Disclosing the structures that generate 2F5-like antibodies may guide future vaccine development.

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Section: F5 Binding To Liposomalsupporting

confidence: 74%

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Serrano

Araujo

Apellániz

et al. 2014

Journal of Biological Chemistry

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“…It is well known that the HBs of water molecules-with the carbonyl oxygen (C = O) and an amide N-H molecular grouptrigger the biomolecular activity of the protein peptides. The most stable water-protein configuration has two HBs: (i) a water proton donor bond to the carbonyl oxygen and (ii) an amide N-H proton donor bond to the water oxygen (29)(30)(31). In protein folding, the water HBs play a role in protein-protein binding and in molecular recognition.…”

Section: Resultsmentioning

confidence: 99%

Energy landscape in protein folding and unfolding

Mallamace

Corsaro

Mallamace

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We use 1 H NMR to probe the energy landscape in the protein folding and unfolding process. Using the scheme ⇄ reversible unfolded (intermediate) → irreversible unfolded (denatured) state, we study the thermal denaturation of hydrated lysozyme that occurs when the temperature is increased. Using thermal cycles in the range 295 < T < 365 K and following different trajectories along the protein energy surface, we observe that the hydrophilic (the amide NH) and hydrophobic (methyl CH 3 and methine CH) peptide groups evolve and exhibit different behaviors. We also discuss the role of water and hydrogen bonding in the protein configurational stability.protein folding | proton NMR | energy landscape | hydration water A n intriguing problem of statistical physics concerns the evolutionary pathways that molecular systems follow as they form mesoscale structures and exhibit new functional behaviors (1). An example of this problem is the self-organization of biosystems that evolve from basic molecules. This challenging subject is studied by using a variety of theoretical methods (2-4). The free-energy landscape model is nowadays the most used to describe such phenomena and especially the aging of the protein folding mechanism (1, 5, 6), i.e., the way in which proteins fold to their native state and then unfold (protein denaturation) (6, 7). The model is based on the idea that in complex materials and systems there are many thermodynamical configurations in which the free-energy surface exhibits a number of local minima separated by barriers, i.e., as the system explores its phase space the trajectory of its evolution is an alternating sequence of local energy minima and saddle points (transition states), which are associated with the positions of all of the system particles. A trajectory thus specifies the path of the system as it evolves by moving across its energy landscape.A peptide is a linear chain of amino acids, and globular proteins are polypeptide chains that fold into their native conformation. During the folding process a polypeptide undergoes many conformational changes and there is a significant decrease in the system configurational entropy as the native state is approached. To understand folding we focus on how proteins search conformational space. The process is accompanied by many microscopic reactions, the nature of which is determined by the specifics of the energy surface. Thus, the characteristics of the energy surface of a polypeptide chain are the key to a quantitative understanding of folding. Although the degrees of freedom of a polypeptide chain allow an enormously large number of possible configurations, "constraints" on the energy decrease these configurations visited in the folding reaction to a limited number (8). Understanding the free-energy surface ("landscape") enables us to understand the folding process. A balance between the potential energy and the configurational entropy leads to a freeenergy barrier that generates the two-state folding behavior usually observed in small proteins. The...

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“…The polarity and composition of the channel walls, particularly in WT M2, are similar to those of an organic solvent, such as ethyl acetate, explaining the favorable partitioning of the adamantane from water to the channel. The structure of the α-helix is particularly favorable for interacting with amantadine-like drugs, because the C = O bonds in solvent-exposed helices are about half-hydrated (39). Thus, they can easily either stabilize an ammonium group when hydrated or dehydrate to stabilize apolar groups, such as adamantane, when dehydrated.…”

Section: Discussionmentioning

confidence: 99%

Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus

Wang

Ma³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

199

350

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The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered smallmolecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.M2-S31N mutant structure | membrane protein structure | M2-S31N inhibitorT he influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine (1-3), which bind directly to the pore of the channel (2-4). Although amantadine has been widely used for several decades, drug resistance has curtailed the use of this family of drugs. Many amantadineresistant influenza viruses can be selected in cell culture (5, 6). A subset of these mutations is found in infected patients undergoing treatment with amantadine (7), and reverse-engineered viruses harboring various pore-lining mutations are competent to replicate in the mouse (8). However, many of these mutations give rise to somewhat attenuated viruses that are less transmissible than WT virus, and they tend to revert in the absence of drug pressure (6, 9). Indeed, large-scale sequencing of transmissible viruses isolated as early as 1918 showed that mutations to pore-lining residues are allowed only within the first turn of the transmembrane (TM) helix at positions 26, 27, and 31 (10). S31N has long been the predominant amantadine-resistant mutation in M2 (11)(12)(13)(14). It predominated in 98-100% of the transmissible amantadineresistant H1N1, H5N1, and H3N2 strains isolated from humans, birds, and swine in the past decade. V27A and L26F are less frequent mutations (10,11,15). Extensive studies of point mutations to the pore-lining residues of M2 have been conducted to understand the paucity of natural variants (16,17). Numerous mutants in the N-terminal aqueous pore retained the ability to conduct protons selectively over other ions, although the magnitude and pH dependence of their conduction varied. However, only a few mutations at the most distal sites, V27A,...

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The hydration of amides in helices; a comprehensive picture from molecular dynamics, IR, and NMR

Cited by 150 publications

References 46 publications

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Structure and Immunogenicity of a Peptide Vaccine, Including the Complete HIV-1 gp41 2F5 Epitope

Energy landscape in protein folding and unfolding

Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus

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