Protein Denaturation and Folding:- Polypeptides Fold Rapidly by a Stepwise Process

In living cells, proteins are assembled from amino acids at a very high rate. For example, E. coli cells can make a complete, biologically active protein molecule containing 100 amino acid residues in about 5 seconds at 37 C. How does such a polypeptide chain arrive at its native conformation? Let’s assume conservatively that each of the amino acid residues could take up 10 different conformations on average, giving 10¹⁰⁰ different conformations for the polypeptide. Let’s also assume that the protein folds itself spontaneously by a random process in which it tries out all possible conformations around every single bond in its backbone until it finds its native, biologically active form. If each conformation were sampled in the shortest possible time (~10^-13 second, or the time required for a single molecular vibration), it would take about 10⁷⁷ years to sample all possible conformations. Thus, protein folding cannot be a completely random, trial-and-error process. There must be shortcuts. This problem was first pointed out by Cyrus Levinthal in 1968 and is sometimes called Levinthal’s paradox. The folding pathway of a large polypeptide chain is unquestionably complicated, and not all the principles that guide the process have been worked out. However, extensive study has led to the development of several plausible models. In one, the folding process is envisioned as hierarchical. Local secondary structures form first. Certain amino acid sequences fold readily into α helices or β sheets, guided by constraints we have re viewed in our discussion of secondary structure. This is followed by longer-range interactions between, say, two α helices that come together to form stable supersec ondary structures. The process continues until complete domains form and the entire polypeptide is folded (Fig. 4–28). In an alternative model, folding is initiated by a spontaneous collapse of the polypeptide into a compact state, mediated by hydrophobic interactions among non-polar residues. The state resulting from this “hydrophobic collapse” may have a high content of secondary structure, but many amino acidside chains are not entirely fixed. The collapsed state is often referred to as a molten globule. Most proteins probably fold by a process that incorporates features of both models. Instead of following a single pathway, a population of pep tide molecules may take a variety of routes to the same end point, with the number of different partly folded conformational species decreasing as folding nears completion.

Thermodynamically, the folding process can be viewed as a kind of free-energy funnel (Fig. 4–29). The unfolded states are characterized by a high degree of conformational entropy and relatively high free energy. As folding proceeds, the narrowing of the funnel represents a decrease in the number of conformational species present. Small depressions along the sides of the free-energy funnel represent semistable intermediates that can briefly slow the folding process. At the bottom of the funnel, an ensemble of folding intermediates has been reduced to a single native conformation (or one of a small set of native conformations). Defects in protein folding may be the molecular basis for a wide range of human genetic disorders. For example, cystic fibrosis is caused by defects in a membrane-bound protein called cystic fibrosis trans membrane conductance regulator (CFTR), which acts as a channel for chloride ions. The most common cystic fibrosis–causing mutation is the deletion of a Phe residue at position 508 in CFTR, which causes improper protein folding (see Box 11–3). Many of the disease related mutations in collagen (p. 129) also cause defective folding. An improved understanding of protein folding may lead to new therapies for these and many other diseases (Box 4–5). ■ Thermodynamic stability is not evenly distributed over the structure of a protein—the molecule has regions of high and low stability. For example, a protein may have two stable domains joined by a segment with lower structural stability, or one small part of a domain may have a lower stability than the remainder. The regions of low stability allow a protein to alter its conformation between two or more states. As we shall see in the next two chapters, variations in the stability of regions within a given protein are often essential to protein function.

FIGURE 4–28 A simulated folding pathway. The folding pathway of a 36-residue segment of the protein villin (an acti-binding protein found principally in the microvilli lining the intestine) was simulated by computer. The process started with the randomly coiled peptide and 3,000 surrounding water molecules in a virtual “water box.” The molecular motions of the peptide and the effects of the water molecules were taken into account in mapping the most likely paths to the final structure among the countless alternatives. The simulated folding took place in a theoretical time span of 1ms; however, the calculation required half a billion integration steps on two Cray supercomputers, each running for two months.

FIGURE 4–29 The thermodynamics of protein folding depicted as a free-energy funnel. At the top, the number of conformations, and hence the conformational entropy, is large. Only a small fraction of the intramolecular interactions that will exist in the native conformation are present. As folding progresses, the thermodynamic path down the funnel reduces the number of states present (decreases entropy), increases the amount of protein in the native conformation, and de creases the free energy. Depressions on the sides of the funnel represent semistable folding intermediates, which may, in some cases, slow the folding process.

may have two stable domains joined by a segment with lower structural stability, or one small part of a domain may have a lower stability than the remainder. The regions of low stability allow a protein to alter its conformation between two or more states. As we shall see in the next two chapters, variations in the stability of regions within a given protein are often essential to protein function.

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شعبة التوجيه الديني النسوي تنظم مسابقة ثقافية بذكرى ولادة السيدة المعصومة (عليها السلام)

المجمع العلمي ينظّم محاضرةً تربوية لطلبة مشروع حفظ القرآن الكريم في كربلاء

قسم الشؤون الفكرية يقيم معرضًا وثائقيًا ضمن مهرجان (الشهيد) في جامعة الكوفة

قسم الشؤون الدينية يشهد إقبالًا واسعًا من المؤمنين لتنظيم عقود الزواج

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الآخبار الصحية

دواء جديد يحمي القلب ويعزز علاج السرطان في آن واحد

سر غذائي بسيط لحماية القلب مع التقدم في العمر

علامات تشير إلى اختلال عمل الغدة الدرقية

السمنة واللقاحات.. دراسة تكشف تأثيراً سلبياً

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صاروخ يطلق قمرا اصطناعيا في مدار خاطئ

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المزيد

مواضيع ذات صلة

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Protein-Ligand Interactions Can Be Described Quantitatively

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Myoglobin Has a Single Binding Site for Oxygen

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Oxygen Can Be Bound to a Heme Prosthetic Group

Protein Denaturation and Folding:- Some Proteins Undergo Assisted Folding

Protein Denaturation and Folding: - Amino Acid Sequence Determines Tertiary Structure

Protein Tertiary and Quaternary Structures: -Protein Quaternary Structures Range from Simple Dimers to Large Complexes

Protein Tertiary and Quaternary Structures: -Protein Motifs Are the Basis for Protein Structural Classification

Protein Tertiary and Quaternary Structures: -Analysis of Many Globular Proteins Reveals Common Structural Patterns

Protein Tertiary and Quaternary Structures:- Globular Proteins Have a Variety of Tertiary Structures

Protein Tertiary and Quaternary Structures:- Myoglobin Provided Early Clues about the Complexity of Globular Protein Structure

Protein Tertiary and Quaternary Structures: -Structural Diversity Reflects Functional Diversity in Globular Proteins

Protein Tertiary and Quaternary Structures: -Fibrous Proteins Are Adapted for a Structural Function