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Introduction to Proteins

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glutamate may undergo hydroxylation on Cβ (β-hydroxylation), whereas aspartate may be γ-carboxylated. — location: 53304 ^ref-55886

this appears to be backwards

histidine the most frequently involved residue in enzyme-mediated catalysis, and with the highest tendency to participate directly in catalysis. — location: 53742 ^ref-8661

[87] — location: 53743 ^ref-57640

Poisson–Boltzmann Equation (PBE), — location: 54617 ^ref-15165

at physiological pH the solubility of proteins is low enough to make their interactions reversible (in accordance with biological needs), but not low enough to promote nonspecific interactions, which would lead to sedimentation. — location: 55052 ^ref-23463

histidine is also capable of P–P interactions. — location: 55489 ^ref-26321

aromatic amino acids are enriched in regions of proteins that function as gates, e.g., in ion channels and enzymes. — location: 55925 ^ref-38326

tryptophan residues tend to appear in binding sites of enzymes and antibodies, where they take part in both the design of the site’s geometry and in protein–ligand interactions. — location: 55928 ^ref-33641

carboxylation of Cγ of glutamate residues. — location: 56363 ^ref-10516

appearing in Ca2+ -binding proteins, — location: 56363 ^ref-22742

(Prothrombin, ProFactor IX, ProFactor X[115]), and which include this modification on 10–12 glutamate residues, use the bound Ca2+to adhere electrostatically to the negatively charged membranes of blood platelets. — location: 56363 ^ref-7746

amino acids are added sequentially from the carboxyl end until the chain is complete. — location: 57236 ^ref-24452

The amino acid sequence of the protein is traditionally presented from left (N-terminus) to right (C-terminus). — location: 57237 ^ref-20173

the free amino group is blocked by an acetyl group, — location: 57672 ^ref-58763

N–H and C = O groups are capable of interacting electrostatically with charged side-chains, with polar groups of the protein’s natural ligand, and with each other. — location: 57674 ^ref-65253

look at the bonds forming the hinges of the chain, since their character determines the freedom of movement of the chain at these locations. — location: 58547 ^ref-63321

trans configuration is 1000 times more stable than the cis, which means the latter is only seldom observed. — location: 58548 ^ref-28360

When the allowed ϕ and ψ values are applied to a model of the protein chain, simple local folds emerge, such as coils, loops, and extended shapes. — location: 59421 ^ref-32299

right-handed helix corresponds to backbone φ and ψ values of –57° and –47°, respectively. — location: 59423 ^ref-12014

pattern of backbone hydrogen bonds along the helical axis (Figure 2.13b). Specifically, each bond is formed between a backbone carbonyl group (C = O) and a backbone amide group (N–H) located four positions downstream in the sequence — location: 61604 ^ref-34199

each turn of the helix accommodating 3.6 residues. — location: 62478 ^ref-30970

it seems that α-helices in proteins are in fact stabilized by nonpolar and van der Waals interactions involving the side-chains of residues, particularly their Cα atom[148,149] — location: 62479 ^ref-47503

acidic glutamate and aspartate residues tend to occupy the N’ of α-helices, where they can favorably interact with the partially positive charge and further stabilize the helix.[153,154] The same happens with basic Lys and Arg residues at the C’. — location: 62481 ^ref-7867

The 310 helix is narrower and longer than the α-helix — location: 63352 ^ref-986

π helix has ϕ and ψ backbone angles of –57° and –70° (respectively),[145] rendering it shorter and wider than the canonical α-helix (Figure 2.15c), with 4.4 residues per turn on average. — location: 63789 ^ref-16127

Like the 310 helix, the π helix also tends to appear at the edges of α-helices, where it occupies no more than a few residues. — location: 63790 ^ref-1580

PPII, can be observed in proteins in their natural aqueous environment. This is a left-handed helix, in which all peptide bonds are in their trans configuration (ϕ, ψ, ω = –75°, + 180°,145°) — location: 63791 ^ref-37421

In folded proteins PPII helices tend to be amphipathic, and therefore reside at the periphery of the globular structure.[50] — location: 63792 ^ref-26825

SH3 — location: 64226 ^ref-24079

The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such asAbl and Src.[1][2

The SH3 domain has a characteristic beta-barrel fold that consists of five or six β-strandsarranged as two tightly packed anti-parallel β sheets. The linker regions may contain short helices. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes.[6]

The classical SH3 domain is usually found in proteins that interact with other proteins and mediate assembly of specific protein complexes, typically via binding to proline-rich peptides in their respective binding partner

PPII helices are common in denatured proteins, — location: 64226 ^ref-58964

the total electrostatic free energy of a system also includes a polarization component. — location: 65974 ^ref-3335

In other words, intramolecular hydrogen bonds do not occur in order to stabilize α-helices and β-sheets, as traditionally argued in many textbooks. Quite the contrary; the secondary structures are used to allow hydrogen-bond formation, thus reducing the high de-solvation cost associated with the transfer of the protein’s backbone groups from the aqueous phase into the low-dielectric core of the protein. Indeed, ~50% of protein residues, and virtually all of them within the core, exist as part of α-helices or β-sheets. — location: 65975 ^ref-42529

the secondary structures are used to allow hydrogen-bond formation, thus reducing the high de-solvation cost associated with the transfer of the protein’s backbone groups from the aqueous phase into the low-dielectric core of the protein. — location: 65976 ^ref-48647

proteins fold in a way that satisfies two requirements. — location: 65976 ^ref-17374

first is tight packing of atoms, — location: 65976 ^ref-24017

needed to maintain compactness and optimize stabilizing interactions. — location: 65976 ^ref-18616

The second is efficient pairing of backbone amide and carbonyl groups in hydrogen bonds, needed to reduce the destabilizing effect of their de-solvation. — location: 65976 ^ref-59299

numerous chemical modifications turn residues often undergo, which increase their chemical diversity and allow fine-tuning of protein–ligand interactions. — location: 66410 ^ref-9637

four residues. Among those, the residue in the second position is usually cis-proline (Pro), whereas the fourth is glycine (Gly) — location: 66411 ^ref-22210

second position is usually cis-proline — location: 66411 ^ref-47055

fourth is glycine — location: 66411 ^ref-4261

two main types of β-turns, differing in the orientation of the peptide bond connecting the second and third residues. — location: 66847 ^ref-16997

of mainly polar residues as the building blocks of loops. — location: 66848 ^ref-43303

antigen-binding site of antibodies, which is discussed in Section 4.2. — location: 66848 ^ref-34371

that the most important factor is the linearity of the side-chain. — location: 67721 ^ref-31857

Membrane proteins are the exception; there, proline residues can be found quite often inside membrane-crossing α-helices, — location: 67723 ^ref-22099

Gly is over-represented at the C-terminus of helices, and is considered a “helix terminator.” — location: 67724 ^ref-28044

N-terminal preference of the negatively charged Asp — location: 68158 ^ref-59209

At the C-termini of both parallel and anti-parallel β-sheets the preferred amino acids are Asp, Asn, Ser, and Pro. — location: 68159 ^ref-39870

The preferred amino acids at the N-terminus of β-sheets are Lys and Arg. — location: 68160 ^ref-4884

fortifying the dipole, — location: 68160 ^ref-22387

This confuses me

The (slightly) preferred residues are Val, Ile, Tyr, Phe, Trp, and Thr. — location: 68160 ^ref-23247

An interesting possibility may be that these residues are preferred not because they stabilize the β structure per se, but rather because they prevent the formation of α-helices in that region. — location: 68595 ^ref-64809

[199] — location: 69034 ^ref-2396

β-sandwich motif builds one of the most common complex folds in proteins, the immunoglobulin fold, — location: 72964 ^ref-55731

each Ig fold is basically a β-sandwich, including nine strands and loops. Interestingly, the specificity of antigen binding is determined by the six loops in the structure (three from each chain), rather than the strands. — location: 72967 ^ref-53237

structural flexibility of the loops increases the variability of the antigen-binding site even beyond the level conferred by sequence variations.[228] That is, the loops are capable of undergoing spontaneous conformational changes, which change the shape of the binding site, and as a result, allow the same antibody to bind different antigens. — location: 73838 ^ref-19017

Biological systems are not isolated. That is, they exist in a state of constant temperature and pressure, not volume and energy. — location: 128453 ^ref-14970

represents the “useful” energy† in systems under constant temperature and pressure. — location: 128453 ^ref-19469

state function: — location: 129326 ^ref-5862

general tendency to minimize energy and maximize disorder. — location: 129327 ^ref-21278

heating a sample containing a macromolecule is not accompanied by a temperature increase (as would normally be expected†), as long as there are intact interactions left within the macromolecule. — location: 131510 ^ref-44716

heat capacity can be viewed as a measure of the number of non-covalent interactions in the system. — location: 131510 ^ref-509

However, in cases where folding involves the burial of non-polar atoms inside the macromolecule (as in the case of proteins), the hydrophobic effect driving this process[9] is accompanied by an increase in the entropy of the aqueous solvent. — location: 131512 ^ref-54243

the increase in solvent entropy over-compensates for the loss of entropy of the macromolecule, thus leading to an overall (favorable) increase in the entropy of the whole system. — location: 131947 ^ref-55361

another definition of ΔS: In an exothermic (heat releasing) process, ΔS expresses the number of molecular states of the surroundings, over which the heat energy can be dispersed, — location: 131947 ^ref-58078

when a system contains a high number of configurational states over which heat can be dispersed, it will take more heat to produce a temperature change, or, in other words, the heat capacity of the system will be higher. — location: 131948 ^ref-44334

implicit models [e.g., the continuum-solvent model (CS)[21]] can be used for calculating free energy values directly — location: 132386 ^ref-5943

state function, — location: 132822 ^ref-2264

Non-polar interactions stabilize only the folded state, whereas protein configurational entropy stabilizes only the unfolded state. — location: 133695 ^ref-58211

that the overall structure of a protein can be maintained even after its sequence is randomized, as long as the original hydrophobic–hydrophilic pattern is kept. — location: 133695 ^ref-14038

controversial due to the molecular interpretation of the measured values. — location: 133696 ^ref-46351

that ΔGnp obtained from the transfer experiments of non-polar amino acids correlated with their surface area — location: 134131 ^ref-63959

non-polar interactions within proteins may differ in strength, depending on the local environment of the interacting residues. — location: 134568 ^ref-26068

two components: The decrease in the number of accessible conformers,* and the decrease in the free movement of atoms within the energy well corresponding to each conformer. — location: 134568 ^ref-36024

studies show that the loss of entropy following protein folding is more significant for the backbone than for the side-chains. — location: 134571 ^ref-4387

Brandts reached a similar conclusion in 1964, following his studies on chymotripsinogen.[29,30] However, he concluded that the two opposable effects are entropy and enthalpy, where in fact, they are both entropic in nature. — location: 134571 ^ref-21777

Electrostatic interactions (ionic, hydrogen bonds) — location: 135005 ^ref-33825

electrostatic interactions within the core of proteins, is a matter of a long dispute. — location: 135442 ^ref-54551

electrostatic interactions include two different contributions: pairwise (Coulomb) interactions between the solute’s charges, and polarization (Born) interactions between solute charges and those of the medium — location: 135443 ^ref-25927

the total effect of the electrostatic interactions on protein folding depends on the magnitude of the ΔGpol vs. ΔGCoul components. — location: 135444 ^ref-63988

unfavorable ΔGpol — location: 135879 ^ref-45296

favorable ΔGCoul — location: 135879 ^ref-28789

the energy of hydrogen bonds also depends on their microenvironment. — location: 136316 ^ref-54743

polar residues that are not in proximity to the substrate. — location: 136317 ^ref-53996

they may change the pKa of the catalytic residues, thus changing their ionization state. — location: 136317 ^ref-12218

His, which, by acting as a general base, decreases the pKa of the catalytic serine’s hydroxyl group, thus allowing it to de-protonate and become a strong nucleophile. — location: 136318 ^ref-30269

importance of electrostatic interactions in promoting the specific fold of the native protein — location: 136753 ^ref-24499

most structural biophysicists consider van der Waals interactions to be secondary to the hydrophobic effect as a driving force of folding. — location: 137189 ^ref-53786

value of the ϕ angle of PPII is similar to that of the α-helix, whereas the value of the ψ angle is similar to that of the β conformation. — location: 137192 ^ref-34616

behavior; at moderate temperatures they occur as a result of changes in the entropy of the aqueous solvent (ΔSwater),[27] as stated in Chapter 1. However, at high temperatures they are driven by changes in the enthalpy of the solvent (ΔHwater; although ΔSwater is still positive). — location: 138064 ^ref-12048

when the solvent pH is lower than the pKa of a residue, it tends to be protonated. — location: 138066 ^ref-31110

When the pH of the solvent is higher than the pKa of a residue, it tends to be de-protonated. — location: 138500 ^ref-28964

pH change must be large enough to create an unfavorable ionization state. — location: 138501 ^ref-5928

of the pKa shift, which is often observed in protein residues and occurs to prevent the unfavorable state — location: 138501 ^ref-2340

sedimentation of 28% of the proteins in a cell leads to its instant death. — location: 138939 ^ref-19045

the contribution of the protein’s surface to protein stability mainly involves electrostatic interactions. — location: 141122 ^ref-37609

N218S, G169A, Y217K, M50F, Q206C, and N76D. — location: 141123 ^ref-34381

when the domains are separated by short limiting linkers, their interactions with each other are not completely satisfied, which makes their effect on the folding rate smaller. — location: 152046 ^ref-53409

α-crystallin, the protein responsible for the transparence of our eyes, and which has always been considered as inert, is also an sHSP. As such, its expression is not limited to the eyes, but also occurs in other tissues, primarily the heart, kidneys, and striated muscles. — location: 152920 ^ref-26656

protein disulfide isomerase (PDI), which catalyzes the formation and reorganization of disulfide bonds inside the ER lumen, — location: 153356 ^ref-46337

The probability of the protein to acquire a certain substate (P) depends inversely and exponentially on its free energy (ΔG), — location: 155540 ^ref-55562

the protein is expected to spend most of the time occupying those substates that have the least energy. — location: 155976 ^ref-14452

proteins, the secondary elements in disordered proteins tend to change or disappear constantly, due to the lack of stabilizing tertiary interactions. — location: 155980 ^ref-55646

The quantum-mechanical (QM) treatment acknowledges that each reactant has a most probable location, but also less probable ones, which may even be on the other side of the reaction’s energy barrier. — location: 157289 ^ref-10823

mutations that have so far eluded scientists due to their distant locations and their non-additive effect on tunneling have been found to act by disrupting the network of coupled vibrations that optimize the tunneling process. — location: 157726 ^ref-3614