Since its introduction, the basin hopping (BH) framework has proven useful for hard nonlinear optimization problems with multiple variables and modalities. Applications span a wide range, from packing problems in geometry to characterization of molecular states in statistical physics. BH is seeing a reemergence in computational structural biology due to its ability to obtain a coarse-grained representation of the protein energy surface in terms of local minima. In this paper, we show that the BH framework is general and versatile, allowing to address problems related to the characterization of protein structure, assembly, and motion due to its fundamental ability to sample minima in a high-dimensional variable space. We show how specific implementations of the main components in BH yield algorithmic realizations that attain state-of-the-art results in the context of ab initio protein structure prediction and rigid protein-protein docking. We also show that BH can map intermediate minima related with motions connecting diverse stable functionally relevant states in a protein molecule, thus serving as a first step towards the characterization of transition trajectories connecting these states.

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Detection of protein complexes and their structures is crucial for understanding their role in the basic biology of organisms. Computational docking methods can provide researchers with a good starting point for the analysis of protein complexes. However, these methods are often not accurate and their results need to be further refined to improve interface packing. In this paper, we introduce a refinement method that incorporates evolutionary information into a novel scoring function by employing Evolutionary Trace (ET)-based scores. Our method also takes Van der Waals interactions into account to avoid atomic clashes in refined structures. We tested our method on docked candidates of eight protein complexes and the results suggest that the proposed scoring function helps bias the search toward complexes with native interactions. We show a strong correlation between evolutionary-conserved residues and correct interface packing. Our refinement method is able to produce structures with better lRMSD (least RMSD) with respect to the known complexes and lower energies than initial docked structures. It also helps to filter out false-positive complexes generated by docking methods, by detecting little or no conserved residues on false interfaces. We believe this method is a step toward better ranking and prediction of protein complexes.

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Structural modeling of molecular assemblies promises to improve our understanding of molecular interactions and biological function. Even when focusing on modeling structures of protein dimers from knowledge of monomeric native structure, docking two rigid structures onto one another entails exploring a large configurational space. This paper presents a novel approach for docking protein molecules and elucidating native-like configurations of protein dimers. The approach makes use of geometric hashing to focus the docking of monomeric units on geometrically complementary regions through rigid-body transformations. This geometry-based approach improves the feasibility of searching the combined configurational space. The search space is narrowed even further by focusing the sought rigid-body transformations around molecular surface regions composed of amino acids with high evolutionary conservation. This condition is based on recent findings, where analysis of protein assemblies reveals that many functional interfaces are significantly conserved throughout evolution. Different search procedures are employed in this work to search the resulting narrowed configurational space. A proof-of-concept energy-guided probabilistic search procedure is also presented. Results are shown on a broad list of 18 protein dimers and additionally compared with data reported by other labs. Our analysis shows that focusing the search around evolutionary-conserved interfaces results in lower lRMSDs.