Advances in Protein Chemistry最新文献

Hydrogen bonding underlies the structure of water and all biochemical processes in aqueous medium. Analysis of modern ab initio wave functions in terms of natural bond orbitals (NBOs) strongly suggests the resonance-type "charge transfer" (CT) character of H-bonding, contrary to the widely held classical-electrostatic viewpoint that underlies current molecular dynamics (MD) modeling technology. Quantum cluster equilibrium (QCE) theory provides an alternative ab initio-based picture of liquid water that predicts proton-ordered two-coordinate H-bonding patterns, dramatically different from the ice-like picture of electrostatics-based MD simulations. Recent X-ray absorption and Raman scattering experiments of Nilsson and co-workers confirm the microstructural two-coordinate picture of liquid water. We show how such cooperative "unsaturated" ring/chain topologies arise naturally from the fundamental resonance-CT nature of B:cdots, three dots, centeredHA hydrogen bonding, which is expressed in NBO language as n(B)-->sigma(AH)(*) intermolecular delocalization from a filled lone pair n(B) of the Lewis base (B:) into the proximal antibond sigma(AH)(*) of the Lewis acid (HA). Stabilizing n(O)-->sigma(OH)(*) orbital delocalization, equivalent to partial mixing of resonance structures H(2)O:cdots, three dots, centeredHOH H(3)O(+) cdots, three dots, centered(-):OH, is thereby seen to be the electronic origin of general enthalpic and entropic propensities that favor relatively small cyclic clusters such as water pentamers W(5c) in the QCE liquid phase. We also discuss the thermodynamically competitive three-coordinate clusters (e.g., icosahedral water buckyballs, W(24)), which appear to play a role in hydrophobic solvation phenomena. We conclude with suggestions for incorporating resonance-CT aspects of H-bonding into empirical MD simulation potentials in a computationally tractable manner.

This chapter discusses methods for modeling electronic polarization in proteins and protein-ligand complexes. Two different approaches are considered: explicit incorporation of polarization into a molecular mechanics force field and the use of mixed quantum mechanics/molecular mechanics methods to model polarization in a restricted region of the protein or protein-ligand complex. A brief description is provided of the computational methodology and parameterization protocols and then results from two preliminary studies are presented. The first study employs quantum mechanics/molecular mechanics (QM/MM) methods to improve the accuracy of protein-ligand docking; here, incorporation of polarization is shown to dramatically improve the robustness of the accuracy of structural prediction of the protein-ligand docking by enabling qualitative improvement in the selection of the correct hydrogen bonding patterns of the docked ligand. The second study discusses a 2-ns simulation of bovine pancreatic trypsin inhibitor (BPTI) in water using a variety of fixed charge and polarizable models for both the protein and the solvent, analyzing observed root mean square deviations (RMSD), intraprotein hydrogen bonding, and water structure and dynamics. All of these efforts are in a relatively early stage of development, the results are encouraging in that stable methods have been developed, and significant effects of polarization are seen and (in the case of the QM/MM-based docking) improvements have been validated as compared to experiment. With regard to accuracy and robustness of full simulations, a great deal more work needs to be done to quantitate and improve the present models.

Since biomolecules exist in aqueous and membrane environments, the accurate modeling of solvation, and hydrogen bonding interactions in particular, is essential for the exploration of structure and function in theoretical and computational studies. In this chapter, we focus on alternatives to explicit solvent models and discuss recent advances in generalized Born (GB) implicit solvent theories. We present a brief review of the successes and shortcomings of the application of these theories to biomolecular problems that are strongly linked to backbone H-bonding and electrostatics. This discussion naturally leads us to explore existing areas for improvement in current GB theories and our approach towards addressing a number of the key issues that remain in the refinement of these models. Specifically, the critical importance of balancing solvation forces and intramolecular forces in GB models is illustrated by examining the influence of backbone hydrogen bond strength and backbone dihedral energetics on conformational equilibria of small peptids.

This chapter reviews formulation and parametrization of molecular mechanics force fields with special attention to technical and inherent problems. Most striking among the shortcomings is the inadequacy of the simple point charge description as a means to describe energy and forces of interactions between polar molecules and between polar groups in macromolecules, including hydrogen bonds. The current state of efforts to improve the description of polar interactions is discussed.

A large number of intermediate filament (IF) chains have now been sequenced. From these data, it has been possible to deduce the main elements of the secondary structure, especially those lying within the central rod domain of the molecule. These conclusions, allied to results obtained from crosslinking studies, have shown that at least four unique but related structures are adopted by the class of structures known generically as intermediate filaments: (1) epidermal and reduced trichocyte keratin; (2) oxidized trichocyte keratin; (3) desmin, vimentin, neurofilaments, and related Type III and IV proteins; and (4) lamin molecules. It would be expected that local differences in sequences of the proteins in these four groups would occur, and that this would ultimately relate to assembly. Site-directed mutagenesis and theoretical methods have now made it possible to investigate these ideas further. In particular, new data have been obtained that allow the role played by some individual amino acids or a short stretch of sequence to be determined. Among the observations catalogued here are the key residues involved in intra- and interchain ionic interactions, as well as those involved in stabilizing some modes of molecular aggregation; the structure and role of subdomains in the head and tail domains; the repeat sequences occurring along the length of the chain and their structural significance; trigger motifs in coiled-coil segments; and helix initiation and termination motifs that terminate the rod domain. Much more remains to be done, not least of which is gaining an increased understanding of the many subtle differences that exist between different IF chains at the sequence level.

The alpha-helix was the first proposed and experimentally confirmed secondary structure. The elegant simplicity of the alpha-helical structure, stabilized by hydrogen bonding between the backbone carbonyl oxygen and the peptide amide four residues away, has captivated the scientific community. In proteins, alpha-helices are also stabilized by the so-called capping interactions that occur at both the C- and the N-termini of the helix. This chapter provides a brief historical overview of the thermodynamic studies of the energetics of helix formation, and reviews recent progress in our understanding of the thermodynamics of helix formation.