Surflex-Dock employs an empirically derived scoring function to rank putative protein-ligand interactions by flexible docking of small molecules to proteins of known structure. The scoring function employed by Surflex was developed purely on the basis of positive data, comprising noncovalent protein-ligand complexes with known binding affinities. Consequently, scoring function terms for improper interactions received little weight in parameter estimation, and an ad hoc scheme for avoiding protein-ligand interpenetration was adopted. We present a generalized method for incorporating synthetically generated negative training data, which allows for rigorous estimation of all scoring function parameters. Geometric docking accuracy remained excellent under the new parametrization. In addition, a test of screening utility covering a diverse set of 29 proteins and corresponding ligand sets showed improved performance. Maximal enrichment of true ligands over nonligands exceeded 20-fold in over 80% of cases, with enrichment of greater than 100-fold in over 50% of cases.

Neuronal activity-dependent processes are believed to mediate the formation of synaptic connections during neocortical development, but the underlying intracellular mechanisms are not known. In the visual system, altering the pattern of visually driven neuronal activity by monocular deprivation induces cortical synaptic rearrangement during a postnatal developmental window, the critical period. Here, using transgenic mice carrying a CRE-lacZ reporter, we demonstrate that a calcium- and cAMP-regulated signaling pathway is activated following monocular deprivation. We find that monocular deprivation leads to an induction of CRE-mediated lacZ expression in the visual cortex preceding the onset of physiologic plasticity, and this induction is dramatically downregulated following the end of the critical period. These results suggest that CRE-dependent coordinate regulation of a network of genes may control physiologic plasticity during postnatal neocortical development.

The adult cerebral cortex can adapt to environmental change. Using monocular deprivation as a paradigm, we find that rapid experience-dependent plasticity exists even in the mature primary visual cortex. However, adult cortical plasticity differs from developmental plasticity in two important ways. First, the effect of adult, but not juvenile monocular deprivation is strongly suppressed by administration of barbiturate just prior to recording visual evoked potentials, suggesting that the effect of adult experience can be inactivated acutely. Second, the effect of deprivation is less persistent over time in adults than in juveniles. This correlates with the known decline in CREB function during maturation of the visual cortex. To compensate for this decline in CREB function, we expressed persistently active VP16-CREB and find that it causes adult plasticity to become persistent. These results suggest that in development and adulthood, the regulation of a trans-synaptic signaling pathway controls the adaptive potential of cortical circuits.A primary function of the brain is to integrate the individual into a continually changing environment. Some aspects of this integration are accomplished through developmental processes, other aspects through learning. Although learning can occur throughout life, many behaviors, from language to sexual behavior, are shaped profoundly by early life experience. In this study, we have examined how the adaptive capacity of the cerebral cortex changes with maturation.A classical model of developmental plasticity is ocular dominance plasticity (Wiesel and Hubel 1963;Hubel and Wiesel 1998). Hubel and Wiesel showed that closing one eye of an infant cat produced a visual cortex dominated by the nondeprived eye. Closing an eye of an adult cat was ineffective. Single-unit studies in a number of mammalian systems, ranging from rodents to primates, have found that ocular dominance plasticity is restricted to a period prior to puberty (Hubel and Wiesel 1970;Blakemore et al. 1978;Olson and Freeman 1980;Issa et al. 1999;Fagiolini and Hensch 2000). The amount of deprivation required to alter the responses of visual cortical neurons depends on the animal's age. In the cat, during the peak of the critical period (4-5 wk of age), as little as 1 d of deprivation is sufficient to cause ocular dominance changes (Olson and Freeman 1975). Near the age of puberty, weeks or months of deprivation are necessary to induce changes observable by single-unit recordings, and the changes are thought to occur only in layers 2 and 3 of the visual cortex (Daw et al. 1992).In the clinical literature, however, there are reports suggesting that improvement of visual acuity can occur in adult patients with amblyopia, a central disorder of visual acuity, following patching of the normal eye (Selenow and Ciuffreda 1986; Saulles 1987; Rutstein and Fuhr 1992; Wick and Wingard 1992). Furthermore, a lengthy period of monocular occlusion caused by a dense cataract (Sloper and Collins 1995) can cause significant changes in visu...