Quantum mechanical analysis of electron tunneling in nine thermally fluctuating cytochrome b562 derivatives reveals two distinct protein-mediated coupling limits. A structure-insensitive regime arises for redox partners coupled through dynamically averaged multiple-coupling pathways (in seven of the nine derivatives) where heme-edge coupling leads to the multiple-pathway regime. A structure-dependent limit governs redox partners coupled through a dominant pathway (in two of the nine derivatives) where axial-ligand coupling generates the single-pathway limit and slower rates. This two-regime paradigm provides a unified description of electron transfer rates in 26 ruthenium-modified heme and blue-copper proteins, as well as in numerous photosynthetic proteins.

A long-standing challenge in electron-transfer theory is to compute accurate rates of long-distance reactions in proteins. We describe an ab initio Hartree-Fock approach to compute electronic-coupling interactions and electron-transfer rates in proteins that allows the favorable comparison with experiment. The method includes the following key features; each is essential for reliable rate computations: (1) summing contributions over multiple tunneling pathways, (2) averaging couplings over thermally accessible protein conformations, (3) describing donor and acceptor electronic structure explicitly, including solvation effects, and averaging coupling over multiple energy-level crossings of the nearly degenerate donor-acceptor ligand-field states, and (4) eliminating basis set artifacts associated with diffuse basis functions. The strong dependence of coupling on donor-acceptor distance and on pathway interferences causes large variations of the computed electron-coupling values with protein geometry, and the strongest coupled conformers dominate the electron-transfer rate. As such, averaging over thermally accessible conformers of the protein and of the redox cofactors is essential. This approach was tested on six ruthenium-modified azurin derivatives using the high temperature nonadiabatic rate expression and compared with simpler pathways, average barrier, and semiempirical INDO models. Results of ab initio Hartree-Fock calculations with a split-valence basis set are in good agreement with the experimental rates. Predicted rates in the longer-distance derivatives are underestimated by 3-8-fold. This analysis indicates that the key ingredients needed for quantitatively reliable protein electron-transfer rate calculations are accessible.

Cyclobutane dimer photolyases are proteins that bind to UVdamaged DNA containing cyclobutane pyrimidine dimer lesions. They repair these lesions by photo-induced electron transfer. The electron donor cofactor of a photolyase is a two-electron-reduced flavin adenine dinucleotide (FADH ؊ ). When FADH ؊ is photo-excited, it transfers an electron from an excited 3 * singlet state to the pyrimidine dimer lesion of DNA. We compute the lowest excited singlet states of FADH ؊ using ab initio (time-dependent density functional theory and time-dependent Hartree-Fock), and semiempirical (INDO͞S configuration interaction) methods. The calculations show that the two lowest 3 * singlet states of FADH ؊ are localized on the side of the flavin ring that is proximal to the dimer lesion of DNA. For the lowest-energy donor excited state of FADH ؊ , we compute the conformationally averaged electronic coupling to acceptor states of the thymine dimer. The coupling calculations are performed at the INDO͞S level, on donor-acceptor cofactor conformations obtained from molecular dynamics simulations of the solvated protein with a thymine dimer docked in its active site. These calculations demonstrate that the localization of the 1 FADH ؊ * donor state on the flavin ring enhances the electronic coupling between the flavin and the dimer by permitting shorter electron-transfer pathways to the dimer that have single through-space jumps. Therefore, in photolyase, the photo-excitation itself enhances the electron transfer rate by moving the electron towards the dimer.

This Perspective describes theoretical studies aimed at understanding the structural and thermal properties of materials in which DNA is used to link gold nanoparticles, or polymers or organic molecules. Particularly in the case of gold nanoparticles, the materials derived from this structural motif have proven to be important for biological sensing and other applications, however additional applications may arise as a result of recent advances in the preparation of crystalline materials based on DNA-linked particles. From a theory perspective these are challenging materials to describe due to the large number of atoms, and the polyelectrolyte character of DNA, however there has been important progress recently using all-atom and coarse-grained molecular dynamics, and with analytical theory. Among topics that we discuss are the structure and density of DNA when attached to gold particles, and the size and melting properties of DNA-linked nanoparticles in different environments.