3D structures of RNAs are the basis for understanding their biological functions. However, experimentally solved RNA 3D structures are very limited in comparison with known RNA sequences up to now. Therefore, many computational methods have been proposed to solve this problem, including our 3dRNA. In recent years, 3dRNA has been greatly improved by adding several important features, including structure sampling, structure ranking and structure optimization under residue-residue restraints. Particularly, the optimization procedure with restraints enables 3dRNA to treat pseudoknots in a new way. These new features of 3dRNA can greatly promote its performance and have been integrated into the 3dRNA v2.0 web server. Here we introduce these new features in the 3dRNA v2.0 web server for the users.

Minimum Free Energy Path (MFEP) is very important in computational biology and chemistry. The barrier in the path is related to the reaction rate, and the start-to-end difference gives the relative stability between reactant and product. All these information is significant to experiment and practical application. But finding MFEP is not an easy job. Lots of degrees of freedom make the computation very complicated and time consuming. In this paper, we use the Steepest Descent Path (SDP) to accelerate the sampling of MFEP. The SHAKE algorithm and the Lagrangian multipliers are used to control the optimization of both SDP and MFEP. These strategies are simple and effective. For the former, it is more interesting. Because as we known, SHAKE algorithm was designed to handle the constraints in molecular dynamics in the past, has never been used in geometry optimization. Final applications on ALA dipeptide and 10-ALA peptide show that this combined optimization method works well. Use the information in SDP, the initial path could reach the more optimal MFEP. So more accurate free energies could be obtained and the amount of computation time could be saved.

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We report on a nonlinear analysis of deterministic structures in Alu repeats, one of the richest repetitive DNA sequences in the human genome. Alu repeats contain the recognition sites for the restriction endonuclease AluI, which is what gives them their name. Using the nonlinear prediction method developed in chaos theory, we find that all Alu repeats have novel deterministic structures and show strong nonlinear correlations that are absent from exon and intron sequences. Furthermore, the deterministic structures of Alus of younger subfamilies show panlike shapes. As young Alus can be seen as mutation free copies from the "master genes," it may be suggested that the deterministic structures of the older subfamilies are results of an evolution from a "panlike" structure to a more diffuse correlation pattern due to mutation.

Minimum Free Energy Path (MFEP) provides a lot of important information about the chemical reactions, like the free energy barrier, the location of the transition state, and the relative stability between reactant and product. With MFEP, one can study the mechanisms of the reaction in an efficient way. Due to a large number of degrees of freedom, searching the MFEP is a very time-consuming process. Here, we present a fast tomographic method to perform the search. Our approach first calculates the free energy surfaces in a sequence of hyperplanes perpendicular to a transition path. Based on an objective function and the free energy gradient, the transition path is optimized in the collective variable space iteratively. Applications of the present method to model systems show that our method is practical. It can be an alternative approach for finding the state-to-state MFEP.

Most inhibitors of Cyclin-dependent kinase 2 (CDK2) target its ATP-binding pocket. It is difficult, however, to use this pocket to design very specific inhibitors because this catalytic pocket is highly conserved in the protein family of CDKs. Here we report some short peptides targeting a noncatalytic pocket near the interface of the CDK2/Cyclin complex. Docking and molecular dynamics simulations were used to select the peptides, and detailed dynamical network analysis revealed that these peptides weaken the complex formation via allosteric interactions. Our experiments showed that upon binding to the noncatalytic pocket, these peptides break the CDK2/Cyclin complex partially and diminish its kinase activity in vitro. The binding affinity of these peptides measured by Surface Plasmon Resonance can reach as low as 0.5 µM.

To understand how symmetric structures of many proteins are formed from asymmetric sequences, the proteins with two repeated beta-trefoil domains in Plant Cytotoxin B-chain family and all presently known beta-trefoil proteins are analyzed by structure-based multi-sequence alignments. The results show that all these proteins have similar key structural residues that are distributed symmetrically in their structures. These symmetric key structural residues are further analyzed in terms of inter-residues interaction numbers and B-factors. It is found that they can be distinguished from other residues and have significant propensities for structural framework. This indicates that these key structural residues may conduct the formation of symmetric structures although the sequences are asymmetric.

Free-energy calculations for high-dimensional systems, such as peptides or proteins, always suffer from a serious sampling problem in a huge conformational space. For such systems, path-based free-energy methods, such as thermodynamic integration or free-energy perturbation, are good choices. However, both of them need sufficient sampling along a predefined transition path, which can only be controlled using restrained or constrained dynamics. Constrained simulations produce more reasonable free-energy profiles than restrained simulations. But calculations of standard constrained dynamics require an explicit expression of reaction coordinates as a function of Cartesian coordinates of all related atoms, which may be difficult to find for the complex transition of biomolecules. In this paper, we propose a practical solution: (1) We use restrained dynamics to define an optimized transition path, divide it into small fragments, and define a virtual reaction coordinate to denote a position along the path. (2) We use constrained dynamics to perform a formal free-energy calculation for each fragment and collect the values together to provide the entire free-energy profile. This method avoids the requirement to explicitly define reaction coordinates in Cartesian coordinates and provides a novel strategy to perform free-energy calculations for biomolecules along any complex transition path.