Theoretical Biochemistry

Processes and Properties of Biological Systems

Leif A. Eriksson

• Publisher: Elsevier Science
• Year: 2001
• Print ISBN:
  9780444502926
• eBook ISBN:
  9780080542706
• Topic: Physical Sciences
• Subtopic: Biochemistry

Theoretical chemistry has been an area of tremendous expansion and development over the past decade; from an approach where we were able to treat only a few atoms quantum mechanically or make fairly crude molecular dynamics simulations, into a discipline with an accuracy and predictive power that has rendered it an essential complementary tool to experiment in basically all areas of science. This volume gives a flavour of the types of problems in biochemistry that theoretical calculations can solve at present, and illustrates the tremendous predictive power these approaches possess.A wide range of computational approaches, from classical MD and Monte Carlo methods, via semi-empirical and DFT approaches on isolated model systems, to Car-Parinello QM-MD and novel hybrid QM/MM studies are covered. The systems investigated also cover a broad range; from membrane-bound proteins to various types of enzymatic reactions as well as inhibitor studies, cofactor properties, solvent effects, transcription and radiation damage to DNA.

Chapter 1

The structure and function of blue copper proteins

Ulf Ryde^a [email protected]; Mats H.M. Olsson^{a a} Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, S-221 00 Lund, Sweden

Kristine Pierloot^b,* ^b Department of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Heverlee-Leuven, Belgium
^* This investigation has been supported by grants from the Swedish Natural Science Research Council, the Flemish Science Foundation, the Concerted Action of the Flemish Government, and by the European Commission through the TMR program (grant ERBFMRXCT960079). It has also been supported by computer resources of the Swedish Council for Planning and Coordination of Research, Parallelldatorcentrum at the Royal Institute of Technology, Stockholm, the National Supercomputer Centre at the University of Linköping, the High Performance Computing Center North at the University of Umeå, and Lunarc at Lund University.

Abstract

Theoretical investigations of the structure and function of the blue copper proteins and the dimeric Cu_A site are described. We have studied the optimum vacuum geometry of oxidised and reduced copper sites, the relative stability of trigonal and tetragonal Cu(II) structures, the relation between the structure and electronic spectra, the reorganisation energy, and reduction potentials. We also compare their electron-transfer properties with those of cytochromes and iron–sulphur clusters. Our calculations give no support to the suggestion that strain plays a significant role in the function of these proteins; on the contrary, our results show that the structures encountered in the proteins are close to their optimal vacuum geometries (within 7 kJ/mole) and that the favourable properties are achieved by an appropriate choice of ligands. We use the density functional B3LYP method for the geometries, multiconfigurational second-order perturbation theory (CASPT2) for calculations of accurate energies and spectra, pointcharge models, continuum approaches, and combined classical and quantum chemical methods for the environment, and classical force-field calculations for estimation of dynamic effects and free energies.

1 INTRODUCTION

The blue copper proteins or cupredoxins are a group of proteins that exhibit a number of unusual properties, viz. a bright blue colour, a narrow hyperfine splitting in the electron spin resonance (ESR) spectra, and high reduction potentials [1–3]. Moreover, crystal structures of these proteins show an extraordinary cupric geometry: The copper ion is bound to the protein in an approximate trigonal plane formed by a cysteine (Cys) thiolate group and two histidine (His) nitrogen atoms. The coordination sphere in most blue-copper sites is completed by one or two axial ligands, typically a methionine (Met) thioether group, but sometimes also a backbone carbonyl oxygen atom (in the azurins) or instead an amide oxygen atom from the side chain of glutamine (in the stellacyanins) [1–4].

The blue copper proteins serve as electron-transfer agents. Their distorted trigonal geometry is intermediate between the tetrahedral coordination preferred by Cu(I) and the tetragonal geometry of most Cu(II) complexes. As a result, the change in geometry when Cu(II) is reduced to Cu(I) is small [2,3,5], which gives a small reorganisation energy and allows for a high rate of electron transfer [6]. These unusual properties, unprecedented in the chemistry of small inorganic complexes, already in the 1960s led to the proposal that the protein forms a rigid structure, which forces the Cu(II) ion into a coordination geometry more similar to that preferred by Cu(I) [7,8]. These hypotheses were later extended into general theories for metalloproteins, suggesting that the protein forces the metal centre into a catalytically poised state, the entatic state theory [9,10] and the induced rack theory [11,12].

However, this suggestion has recently been challenged [13,14], In particular, we have shown by quantum chemical calculations that the cupric geometry in the blue copper proteins is very close to the optimal vacuum structure of a Cu(II) ion with the same ligands [14]. Why then are the properties of the blue copper proteins so unusual, if not by protein strain? During the last five years, we have tried to answer this question using theoretical methods. In this review, we describe our results and discuss them in relation to the strain hypotheses. We also compare the blue copper proteins with related metal sites, such as the Cu_A dimer, cytochromes, and iron–sulphur clusters. Altogether, this gives an illustration of how theoretical methods, ranging from high-level quantum chemical calculations to pure classical simulations, can be used to study and solve biochemical problems.

2 METHODS

It is not yet possible to perform accurate quantum chemical calculations on a whole protein. Therefore models have to be constructed that are as realistic as possible but at the same time computationally tractable. We have used a number of techniques, ranging from high-level quantum chemical calculations on small models of the active site to classical simulations of the full protein. At the ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright page
• Forword
• Chapter 1: The structure and function of blue copper proteins
• Chapter 2: Myoglobin
• Chapter 3: Mechanisms for enzymatic reactions involving formation or cleavage of O-O bonds
• Chapter 4: Catalytic Reactions of Radical Enzymes
• Chapter 5: Theoretical studies of coenzyme B12-dependent carbon-skeleton rearrangements
• Chapter 6: Simulations of Enzymatic Systems: Perspectives from Car-Parrinello Molecular Dynamics Simulations
• Chapter 7: Computational enzymology: Protein tyrosine phosphatase reactions
• Chapter 8: Monte Carlo simulations of HIV-1 protease binding dynamics and thermodynamics with ensembles of protein conformations: Incorporating protein flexibility in deciphering mechanisms of molecular recognition
• Chapter 9: Modelling G-protein coupled receptors
• Chapter 10: Protein-DNA interactions in the initiation of transcription: The Role of Flexibility and Dynamics of the TATA Recognition Sequence and the TATA Box Binding Protein
• Chapter 11: A multi-component model for radiation damage to DNA from its constituents
• Chapter 12: New computational strategies for the quantum mechanical study of biological systems in condensed phases
• Chapter 13: Modelling Enzyme - Ligand Interactions
• Chapter 14: The QM/MM Approach to Enzymatic Reactions
• Chapter 15: Quinones and quinoidal radicals in photosynthesis
• Author Index
• Subject Index