We present a new computational method of docking pairs of proteins by using spherical polar Fourier correlations to accelerate the search for candidate low-energy conformations. Interaction energies are estimated using a hydrophobic excluded volume model derived from the notion of "overlapping surface skins," augmented by a rigorous but "soft" model of electrostatic complementarity. This approach has several advantages over former three-dimensional grid-based fast Fourier transform (FFT) docking correlation methods even though there is no analogue to the FFT in a spherical polar representation. For example, a complete search over all six rigid-body degrees of freedom can be performed by rotating and translating only the initial expansion coefficients, many unfeasible orientations may be eliminated rapidly using only low-resolution terms, and the correlations are easily localized around known binding epitopes when this knowledge is available. Typical execution times on a single processor workstation range from 2 hours for a global search (5 x 10(8) trial orientations) to a few minutes for a local search (over 6 x 10(7) orientations). The method is illustrated with several domain dimer and enzyme-inhibitor complexes and 20 large antibody-antigen complexes, using both the bound and (when available) unbound subunits. The correct conformation of the complex is frequently identified when docking bound subunits, and a good docking orientation is ranked within the top 20 in 11 out of 18 cases when starting from unbound subunits. Proteins 2000;39:178-194.

We present a new computational method of docking pairs of proteins by using spherical polar Fourier correlations to accelerate the search for candidate low-energy conformations. Interaction energies are estimated using a hydrophobic excluded volume model derived from the notion of "overlapping surface skins," augmented by a rigorous but "soft" model of electrostatic complementarity. This approach has several advantages over former three-dimensional grid-based fast Fourier transform (FFT) docking correlation methods even though there is no analogue to the FFT in a spherical polar representation. For example, a complete search over all six rigid-body degrees of freedom can be performed by rotating and translating only the initial expansion coefficients, many unfeasible orientations may be eliminated rapidly using only low-resolution terms, and the correlations are easily localized around known binding epitopes when this knowledge is available. Typical execution times on a single processor workstation range from 2 hours for a global search (5 x 10(8) trial orientations) to a few minutes for a local search (over 6 x 10(7) orientations). The method is illustrated with several domain dimer and enzyme-inhibitor complexes and 20 large antibody-antigen complexes, using both the bound and (when available) unbound subunits. The correct conformation of the complex is frequently identified when docking bound subunits, and a good docking orientation is ranked within the top 20 in 11 out of 18 cases when starting from unbound subunits. Proteins 2000;39:178-194.

A procedure that rapidly generates an approximate parametric representation of macromolecular surface shapes is described. The parametrization is expressed as an expansion of real spherical harmonic basis functions. The advantage of using a parametric representation is that a pair of surfaces can be matched by using a quasi-Newton algorithm to minimize a suitably chosen objective function. Spherical harmonics are a natural and convenient choice of basis function when the task is one of search in a rotational search space. In particular, rotations of a molecular surface can be simulated by rotating only the harmonic expansion coefficients. This rotational property is applied for the first time to the 3-dimensional molecular similarity problem in which a pair of similar macromolecular surfaces are to be maximally superposed. The method is demonstrated with the superposition of antibody heavy chain variable domains. Special attention is given to computational efficiency. The spherical harmonic expansion coefficients are determined using fast surface sampling and integration schemes based on the tessellation of a regular icosahedron. Low resolution surfaces can be generated and displayed in under 10 s and a pair of surfaces can be maximally superposed in under 3 s on a contemporary workstation. ᮊ

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Background: The translational efficiency of an mRNA can be modulated by upstream open reading frames (uORFs) present in certain genes. A uORF can attenuate translation of the main ORF by interfering with translational reinitiation at the main start codon. uORFs also occur by chance in the genome, in which case they do not have a regulatory role. Since the sequence determinants for functional uORFs are not understood, it is difficult to discriminate functional from spurious uORFs by sequence analysis.