Guang Song

Protein elastic network models and the ranges of cooperativity.

Elastic network models (ENMs) are entropic models that have demonstrated in many previous studies their abilities to capture overall the important internal motions, with comparisons having been made against crystallographic B-factors and NMR conformational variabilities. ENMs have become an increasingly important tool and have been widely used to comprehend protein dynamics, function, and even conformational changes. However, reliance upon an arbitrary cutoff distance to delimit the range of interactions has presented a drawback for these models, because the optimal cutoff values can differ somewhat from protein to protein and can lead to quirks such as some shuffling in the order of the normal modes when applied to structures that differ only slightly. Here, we have replaced the requirement for a cutoff distance and introduced the more physical concept of inverse power dependence for the interactions, with a set of elastic network models that are parameter-free, with the distance cutoff removed. For small fluctuations about the native forms, the power dependence is the inverse square, but for larger deformations, the power dependence may become inverse 6th or 7th power. These models maintain and enhance the simplicity and generality of the original ENMs, and at the same time yield better predictions of crystallographic B-factors (both isotropic and anisotropic) and of the directions of conformational transitions. Thus, these parameter-free ENMs can be models of choice whenever elastic network models are used.

Close correspondence between the motions from principal component analysis of multiple HIV-1 protease structures and elastic network modes.

The large number of available HIV-1 protease structures provides a remarkable sampling of conformations of the different conformational states, which can be viewed as direct structural information about the dynamics of the HIV-1 protease. After structure matching, we apply principal component analysis (PCA) to obtain the important apparent motions for both bound and unbound structures. There are significant similarities between the first few key motions and the first few low-frequency normal modes calculated from a static representative structure with an elastic network model (ENM), strongly suggesting that the variations among the observed structures and the corresponding conformational changes are facilitated by the low-frequency, global motions intrinsic to the structure. Similarities are also found when the approach is applied to an NMR ensemble, as well as to molecular dynamics (MD) trajectories. Thus, a sufficiently large number of experimental structures can directly provide important information about protein dynamics, but ENM can also provide similar sampling of conformations.

Using motion planning to map protein folding landscapes and analyze folding kinetics of known native structures

We present a novel approach for studying the kinetics of protein folding. The framework has evolved from robotics motion planning techniques called probabilistic roadmap methods (prms) that have been applied in many diverse fields with great success. In our previous work, we used a Prm-based technique to study protein folding pathways of several small proteins and obtained encouraging results. In this paper, we describe how our motion planning framework can be used to study protein folding kinetics. In particular, we present a refined version of our Prm-based framework and describe how it can be used to produce potential energy landscapes, free energy landscapes, and many folding pathways all from a single roadmap which is computed in a few hours on a desktop PC. Results are presented for 14 proteins. Our ability to produce large sets of unrelated folding pathways may potentially provide crucial insight into some aspects of folding kinetics, such as proteins that exhibit both two-state and three-state kinetics, that are not captured by other theoretical techniques.

A motion-planning approach to folding: from paper craft to protein folding

We present a framework for studying folding problems from a motion planning perspective. Modeling foldable objects as tree-like multi-link objects allows one to apply motion planning techniques to folding problems. An important feature of this approach is that it not only allows one to study foldability questions, such as, can an object be folded (or unfolded) into another object, but also provides one with another tool for investigating the dynamic folding process itself. The framework proposed here has application to traditional motion planning areas such as automation and animation, and presents a novel approach for studying protein folding pathways. Preliminary experimental results with traditional paper crafts (e.g., box folding) and small proteins (approximately 60 residues) are quite encouraging.

Enhancing randomized motion planners: exploring with haptic hints

In this paper, we investigate methods for enabling a human operator and an automatic motion planner to cooperatively solve a motion planning query. Our work is motivated by our experience that automatic motion planners sometimes fail due to the difficulty of discovering ‘critical’ configurations of the robot that are often naturally apparent to a human observer.Our goal is to develop techniques by which the automatic planner can utilize (easily generated) user-input, and determine ‘natural’ ways to inform the user of the progress made by the motion planner. We show that simple randomized techniques inspired by probabilistic roadmap methods are quite useful for transforming approximate, user-generated paths into collision-free paths, and describe an iterative transformation method which enables one to transform a solution for an easier version of the problem into a solution for the original problem. We also illustrate that simple visualization techniques can provide meaningful representations of the planners progress in a 6-dimensional C-space. We illustrate the utility of our methods on difficult problems involving complex 3D CAD Models.

Using motion planning to study protein folding pathways.

We present a framework for studying protein folding pathways and potential landscapes which is based on techniques recently developed in the robotics motion planning community. Our focus in this work is to study the protein folding mechanism assuming we know the native fold. That is, instead of performing fold prediction, we aim to study issues related to the folding process, such as the formation of secondary and tertiary structure, and the dependence of the folding pathway on the initial denatured conformation. Our work uses probabilistic roadmap (PRM) motion planning techniques which have proven successful for problems involving high-dimensional configuration spaces. A strength of these methods is their efficiency in rapidly covering the planning space without becoming trapped in local minima. We have applied our PRM technique to several small proteins (~60 residues) and validated the pathways computed by comparing the secondary structure formation order on our paths to known hydrogen exchange experimental results. An advantage of the PRM framework over other simulation methods is that it enables one to easily and efficiently compute folding pathways from any denatured starting state to the (known) native fold. This aspect makes our approach ideal for studying global properties of the proteins potential landscape, most of which are difficult to simulate and study with other methods. For example, in the proteins we study, the folding pathways starting from different denatured states sometimes share common portions when they are close to the native fold, and moreover, the formation order of the secondary structure appears largely independent of the starting denatured conformation. Another feature of our technique is that the distribution of the sampled conformations is correlated with the formation of secondary structure and, in particular, appears to differentiate situations in which secondary structure clearly forms first and those in which the tertiary structure is obtained more directly. Overall, our results applying PRM techniques are very encouraging and indicate the promise of our approach for studying proteins for which experimental results are not available.

An enhanced elastic network model to represent the motions of domain-swapped proteins.

Domain swapping is a process where two (or more) protein molecules form a dimer (or higher oligomer) by exchanging an identical domain. In this article, based on the observation that domains are rigid and hinge loops are highly flexible, we propose a new Elastic Network Model, domain‐ENM, for domain‐swapped proteins. In this model, the rigidity of domains is taken into account by using a larger spring constant for intradomain contacts. The large‐scale transition of domain swapping is then novelly decomposed into the relative motion between the rigid domains (only 6 degrees of freedom) plus the internal fluctuations of each domain. Consequently, this approach has the potential to produce much more meaningful transition pathways than other simulation approaches that try to find pathways in a search space of large numbers of dimensions. In this article, we also propose a new way to define the overlap measure. Past approaches used an inappropriate comparison of the large‐scale conformation displacement against the computed infinitesimal motions of modes. Here, we propose an infinitesimal version of the large‐scale conformation change and then compare it with the modes of motions. As a result, we obtain much better overlap values. Using this new overlap definition, we are also able for the first time to give a clear, intuitive explanation why “open” forms tend to produce better overlap values than “closed” forms with traditional ENMs. Finally, as an application, we present a simple approach to show how domain‐ENM can be used to generated transition pathways for domain‐swapped proteins. Proteins 2006.

Customizing PRM roadmaps at query time

We propose an approach for building and querying probabilistic roadmaps. In the roadmap construction stage, we build coarse roadmaps by performing only an approximate validation of the roadmap nodes and/or edges. In the query stage, the roadmap is validated and refined only in the area of interest for the query, and moreover is customized in accordance with any specified query preferences. This approach, which postpones some of the validation checks (e.g., collision checks) to the query phase, yields more efficient solutions to many problems. An important benefit of our approach is that it gives one the ability to customize the same roadmap in accordance with multiple, variable, query preferences. For example our approach enables one to find a path which maintains a particular clearance, or makes at most some specified number of sharp turns. Our preliminary results on problems drawn from diverse application domains show that this new approach dramatically improves performance, and shows remarkable flexibility when adapting to different query requirements.

Using motion planning to map protein folding landscapes and analyze folding kinetics of known native structures.

We investigate a novel approach for studying the kinetics of protein folding. Our framework has evolved from robotics motion planning techniques called probabilistic roadmap methods (PRMs) that have been applied in many diverse fields with great success. In our previous work, we presented our PRM-based technique and obtained encouraging results studying protein folding pathways for several small proteins. In this paper, we describe how our motion planning framework can be used to study protein folding kinetics. In particular, we present a refined version of our PRM-based framework and describe how it can be used to produce potential energy landscapes, free energy landscapes, and many folding pathways all from a single roadmap which is computed in a few hours on a desktop PC. Results are presented for 14 proteins. Our ability to produce large sets of unrelated folding pathways may potentially provide crucial insight into some aspects of folding kinetics, such as proteins that exhibit both two-state and three-state kinetics that are not captured by other theoretical techniques.

Protein folding by motion planning

We investigate a novel approach for studying protein folding that has evolved from robotics motion planning techniques called probabilistic roadmap methods (PRMs). Our focus is to study issues related to the folding process, such as the formation of secondary and tertiary structures, assuming we know the native fold. A feature of our PRM-based framework is that the large sets of folding pathways in the roadmaps it produces, in just a few hours on a desktop PC, provide global information about the proteins energy landscape. This is an advantage over other simulation methods such as molecular dynamics or Monte Carlo methods which require more computation and produce only a single trajectory in each run. In our initial studies, we obtained encouraging results for several small proteins. In this paper, we investigate more sophisticated techniques for analyzing the folding pathways in our roadmaps. In addition to more formally revalidating our previous results, we present a case study showing that our technique captures known folding differences between the structurally similar proteins G and L.