On the energy components governing molecular recognition in the framework of continuum approaches

Molecular recognition is a process that brings together several biological macromolecules to form a complex and one of the most important characteristics of the process is the binding free energy. Various approaches exist to model the binding free energy, provided the knowledge of the 3D structures of bound and unbound molecules. Among them, continuum approaches are quite appealing due to their computational efficiency while at the same time providing predictions with reasonable accuracy. Here we review recent developments in the field emphasizing on the importance of adopting adequate description of physical processes taking place upon the binding. In particular, we focus on the efforts aiming at capturing some of the atomistic details of the binding phenomena into the continuum framework. When possible, the energy components are reviewed independently of each other. However, it is pointed out that rigorous approaches should consider all energy contributions on the same footage. The two major schemes for utilizing the individual energy components to predict binding affinity are outlined as well

Ricci Curvature of the Internet Topology

Analysis of Internet topologies has shown that the Internet topology has negative curvature, measured by Gromov's "thin triangle condition", which is tightly related to core congestion and route reliability. In this work we analyze the discrete Ricci curvature of the Internet, defined by Ollivier, Lin, etc. Ricci curvature measures whether local distances diverge or converge. It is a more local measure which allows us to understand the distribution of curvatures in the network. We show by various Internet data sets that the distribution of Ricci cuvature is spread out, suggesting the network topology to be non-homogenous. We also show that the Ricci curvature has interesting connections to both local measures such as node degree and clustering coefficient, global measures such as betweenness centrality and network connectivity, as well as auxilary attributes such as geographical distances. These observations add to the richness of geometric structures in complex network theory.Comment: 9 pages, 16 figures. To be appear on INFOCOM 201

Cytoplasmic dynein binding, run length, and velocity are guided by long-range electrostatic interactions

Dyneins are important molecular motors involved in many essential biological processes, including cargo transport along microtubules, mitosis, and in cilia. Dynein motility involves the coupling of microtubule binding and unbinding to a change in the configuration of the linker domain induced by ATP hydrolysis, which occur some 25 nm apart. This leaves the accuracy of dynein stepping relatively inaccurate and susceptible to thermal noise. Using multi-scale modeling with a computational focusing technique, we demonstrate that the microtubule forms an electrostatic funnel that guides the dynein’s microtubule binding domain (MTBD) as it finally docks to the precise, keyed binding location on the microtubule. Furthermore, we demonstrate that electrostatic component of the MTBD’s binding free energy is linearly correlated with the velocity and run length of dynein, and we use this linearity to predict the effect of mutating each glutamic and aspartic acid located in MTBD domain to alanine. Lastly, we show that the binding of dynein to the microtubule is associated with conformational changes involving several helices, and we localize flexible hinge points within the stalk helices. Taken all together, we demonstrate that long range electrostatic interactions bring a level of precision to an otherwise noisy dynein stepping process

Highly Efficient and Exact Method for Parallelization of Grid-Based Algorithms and its Implementation in DelPhi

The Gauss–Seidel (GS) method is a standard iterative numerical method widely used to solve a system of equations and, in general, is more efficient comparing to other iterative methods, such as the Jacobi method. However, standard implementation of the GS method restricts its utilization in parallel computing due to its requirement of using updated neighboring values (i.e., in current iteration) as soon as they are available. Here, we report an efficient and exact (not requiring assumptions) method to parallelize iterations and to reduce the computational time as a linear/nearly linear function of the number of processes or computing units. In contrast to other existing solutions, our method does not require any assumptions and is equally applicable for solving linear and nonlinear equations. This approach is implemented in the DelPhi program, which is a finite difference Poisson–Boltzmann equation solver to model electrostatics in molecular biology. This development makes the iterative procedure on obtaining the electrostatic potential distribution in the parallelized DelPhi several folds faster than that in the serial code. Further, we demonstrate the advantages of the new parallelized DelPhi by computing the electrostatic potential and the corresponding energies of large supramolecular structures

Using DelPhi Capabilities to Mimic Protein\u27s Conformational Reorganization with Amino Acid Specific Dielectric Constants

Many molecular events are associated with small or large conformational changes occurring in the corresponding proteins. Modeling such changes is a challenge and requires significant amount of computing time. From point of view of electrostatics, these changes can be viewed as a reorganization of local charges and dipoles in response to the changes of the electrostatic field, if the cause is insertion or deletion of a charged amino acid. Here we report a large scale investigation of modeling the changes of the folding energy due to single mutations involving charged group. This allows the changes of the folding energy to be considered mostly electrostatics in origin and to be calculated with DelPhi assigning residue-specific value of the internal dielectric constant of protein. The predicted energy changes are benchmarked against experimentally measured changes of the folding energy on a set of 257 single mutations. The best fit between experimental values and predicted changes is used to find out the effective value of the internal dielectric constant for each type of amino acid. The predicted folding free energy changes with the optimal, amino acid specific, dielectric constants are within RMSD=0.86 kcal/mol from experimentally measured changes

Analyzing Effects of Naturally Occurring Missense Mutations

Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well

E-hooks provide guidance and a soft landing for the microtubule binding domain of dynein

Macromolecular binding is a complex process that involves sensing and approaching the binding partner, adopting the proper orientation, and performing the physical binding. We computationally investigated the role of E-hooks, which are intrinsically disordered regions (IDRs) at the C-terminus of tubulin, on dynein microtubule binding domain (MTBD) binding to the microtubule as a function of the distance between the MTBD and its binding site on the microtubule. Our results demonstrated that the contacts between E-hooks and the MTBD are dynamical; multiple negatively charted patches of amino acids on the E-hooks grab and release the same positively charged patches on the MTBD as it approaches the microtubule. Even when the distance between the MTBD and the microtubule was greater than the E-hook length, the E-hooks sensed and guided MTBD via long-range electrostatic interactions in our simulations. Moreover, we found that E-hooks exerted electrostatic forces on the MTBD that were distance dependent; the force pulls the MTBD toward the microtubule at long distances but opposes binding at short distances. This mechanism provides a “soft-landing” for the MTBD as it binds to the microtubule. Finally, our analysis of the conformational states of E-hooks in presence and absence of the MTBD indicates that the binding process is a mixture of the induced-fit and lock-and-key macromolecular binding hypotheses. Overall, this novel binding mechanism is termed “guided-soft-binding” and could have broad-reaching impacts on the understanding of how IDRs dock to structured proteins

Experimental Simulation of Symmetry-Protected Higher-Order Exceptional Points with Single Photons

Exceptional points (EPs) of non-Hermitian (NH) systems have recently attracted increasing attention due to their rich phenomenology and intriguing applications. Compared to the predominantly studied second-order EPs, higher-order EPs have been assumed to play a much less prominent role because they generically require the tuning of more parameters. Here we experimentally simulate two-dimensional topological NH band structures using single-photon interferometry, and observe topologically stable third-order EPs obtained by tuning only two real parameters in the presence of symmetry. In particular, we explore how different symmetries stabilize qualitatively different third-order EPs: the parity-time symmetry leads to a generic cube-root dispersion, while a generalized chiral symmetry implies a square-root dispersion coexisting with a flat band. Additionally, we simulate fourfold degeneracies, composed of the non-defective twofold degeneracies and second-order EPs. Our work reveals the abundant and conceptually richer higher-order EPs protected by symmetries and offers a versatile platform for further research on topological NH systems.Comment: 15 pages, 9 figure

Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease-causing mutations

The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin’s function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required

RIS-Aided Wireless Communications: Prototyping, Adaptive Beamforming, and Indoor/Outdoor Field Trials

The prospects of using a Reconfigurable Intelligent Surface (RIS) to aid wireless communication systems have recently received much attention from academia and industry. Most papers make theoretical studies based on elementary models, while the prototyping of RIS-aided wireless communication and real-world field trials are scarce. In this paper, we describe a new RIS prototype consisting of 1100 controllable elements working at 5.8 GHz band. We propose an efficient algorithm for configuring the RIS over the air by exploiting the geometrical array properties and a practical receiver-RIS feedback link. In our indoor test, where the transmitter and receiver are separated by a 30 cm thick concrete wall, our RIS prototype provides a 26 dB power gain compared to the baseline case where the RIS is replaced by a copper plate. A 27 dB power gain was observed in the short-distance outdoor measurement. We also carried out long-distance measurements and successfully transmitted a 32 Mbps data stream over 500 m. A 1080p video was live-streamed and it only played smoothly when the RIS was utilized. The power consumption of the RIS is around 1 W. Our paper is vivid proof that the RIS is a very promising technology for future wireless communications.Comment: 13 pages, 18 figures, submitte