Avidin-biotin is one of the strongest protein-ligand binding systems, with broad applications in biomedical science. Here we report a quantum-based computational study to help elucidate the mechanism of binding avidin to biotin (BTN1) and its close analogue, 2'-iminobiotin (BTN2). Our study reveals that electronic polarization of protein plays a critical role in stabilizing the beta sheet (Thr113-Arg122) at the binding site and makes a substantial contribution to the free energy of avidin-biotin binding. The current finding is in contradiction to the previous notion that electrostatic interaction has no effect on or makes an unfavorable contribution to the free energy of avidin-biotin binding. Our calculations also show that the difference in binding free energy of avidin to BTN1 and BTN2 is almost entirely due to the contribution of electrostatic interaction resulting from polarization-induced stabilization of a hydrogen bond between avidin and BTN1. The current result provides strong evidence that protein polarization accounts for the electrostatic contribution to binding free energy that was missing in previous studies of avidin-biotin binding.

Residents of two villages in Zhejiang Province, China, were interviewed and serum samples were collected to assess prevalence of hantavirus infection. Antibody prevalence was 12% (219/1811), with a ratio of illness to infection of 1.0:5.4. Seroprevalence increased with age, but no association was found with sex. There was also no evidence of vertical transmission. One year later, 2.3% (30/1325) of seronegative subjects had seroconverted including 2 who had hemorrhagic fever with renal syndrome. Peak incidence of infection occurred in those 15-39 years old. Hantaan was the dominant serotype; Seoul serotype was less common (5:1). Host reservoirs were Apodemus agrarius in agricultural fields and Rattus norvegicus in houses. Risk factors for infection were traces of rat-contaminated food, travel to other areas for farm work, direct rodent contact, camping in grain fields, living in a house on the periphery of a village, stacking straw stacks outside houses, and keeping cats. All may provide exposure to infectious rodent reservoirs.

Structures and dynamics of a recently designed dizinc metalloprotein (DFsc) (J. Mol. Biol. 2003, 334, 1101) are studied by molecular dynamics simulation using a dynamically adapted polarized force field derived from fragment quantum calculation for protein in solvent. To properly describe the effect of charge transfer and polarization in the present approach, quantum chemistry calculation of the zinc-binding group is periodically performed (on-the-fly) to update the atomic charges of the zinc-binding group during the MD simulation. Comparison of the present result with those obtained from simulations under standard AMBER force field reveals that charge transfer and polarization are critical to maintaining the correct asymmetric metal coordination in the DFsc. Detailed analysis of the result also shows that dynamic fluctuation of the zinc-binding group facilitates solvent interaction with the zinc ions. In particular, the dynamic fluctuation of the zinc-zinc distance is shown to be an important feature of the catalytic function of the di-ion zinc-binding group. Our study demonstrates that the dynamically adapted polarization approach is computationally practical and can be used to study other metalloprotein systems.

The origin of strong affinity of biotin and its analogs binding to (strept)avidin is still the subject of an ongoing controversy. In this work, thermodynamic integration is carried out to study of the difference of binding free energies between biotin and iminobiotin to streptavidin. Three atomic charge schemes are implemented and compared. One is the traditional AMBER charge, and the other two, termed the polarized protein-specific charge, are based on a linear scaling quantum mechanical method and a continuous solvation model and have polarization effect partially or fully included. The result indicates that when nonpolarized AMBER force field is applied, the result is much underestimated. When electronic polarization is gradually included, the difference of binding affinity increases along with it. Using the linear-response approximation to eliminate the error in self-charging process, the corrected binding affinity agrees well with the experimental observation. This study is direct evidence indicating that polarization effect is critical for the strong binding in streptavidin-biotin system.

No abstract