SEEKR2: Versatile Multiscale Milestoning Utilizing the OpenMM Molecular Dynamics Engine.
Ontology highlight
ABSTRACT:
SUBMITTER: Votapka LW
PROVIDER: S-EPMC9277580 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged spherical receptor and verified the estimated value with Smoluchowski theory. We also calculated the kon rate constant for superoxide dismutase with its natural substrate, O2-, in a validation of a previous experiment using similar methods but with a number of important improvements. We also calculated the kon for a new system: the N-terminal domain of Troponin C with its natural substrate Ca2+. The kon calculated for the latter two systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable when compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor.
| S-EPMC4624728 | biostudies-literature
Project description:Many processes important to chemistry, materials science, and biology cannot be described without considering electronic and nuclear-level dynamics and their coupling to slower, cooperative motions of the system. These inherently multiscale problems require computationally efficient and accurate methods to converge statistical properties. In this paper, a method is presented that uses data directly from condensed phase ab initio simulations to develop reactive molecular dynamics models that do not require predefined empirical functions. Instead, the interactions used in the reactive model are expressed as linear combinations of interpolating functions that are optimized by using a linear least-squares algorithm. One notable benefit of the procedure outlined here is the capability to minimize the number of parameters requiring nonlinear optimization. The method presented can be generally applied to multiscale problems and is demonstrated by generating reactive models for the hydrated excess proton and hydroxide ion based directly on condensed phase ab initio molecular dynamics simulations. The resulting models faithfully reproduce the water-ion structural properties and diffusion constants from the ab initio simulations. Additionally, the free energy profiles for proton transfer, which is sensitive to the structural diffusion of both ions in water, are reproduced. The high fidelity of these models to ab initio simulations will permit accurate modeling of general chemical reactions in condensed phase systems with computational efficiency orders of magnitudes greater than currently possible with ab initio simulation methods, thus facilitating a proper statistical sampling of the coupling to slow, large-scale motions of the system.
| S-EPMC3432097 | biostudies-other
Project description:OpenMM is a molecular dynamics simulation toolkit with a unique focus on extensibility. It allows users to easily add new features, including forces with novel functional forms, new integration algorithms, and new simulation protocols. Those features automatically work on all supported hardware types (including both CPUs and GPUs) and perform well on all of them. In many cases they require minimal coding, just a mathematical description of the desired function. They also require no modification to OpenMM itself and can be distributed independently of OpenMM. This makes it an ideal tool for researchers developing new simulation methods, and also allows those new methods to be immediately available to the larger community.
| S-EPMC5549999 | biostudies-literature
Project description:Efficient prediction and ranking of small molecule binders by their kinetic ( kon and koff) and thermodynamic ( ? G) properties can be a valuable metric for drug lead optimization, as these quantities are often indicators of in vivo efficacy. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon's, koff's, and ? G's. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, ?-cyclodextrin, based on predicted kon's and koff's. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long time scale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and ? G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish "best practices" for its future use.
| S-EPMC6443090 | biostudies-literature
Project description:Internal coordinates such as bond lengths, bond angles, and torsion angles (BAT) are natural coordinates for describing a bonded molecular system. However, the molecular dynamics (MD) simulation methods that are widely used for proteins, DNA, and polymers are based on Cartesian coordinates owing to the mathematical simplicity of the equations of motion. However, constraints are often needed with Cartesian MD simulations to enhance the conformational sampling. This makes the equations of motion in the Cartesian coordinates differential-algebraic, which adversely impacts the complexity and the robustness of the simulations. On the other hand, constraints can be easily placed in BAT coordinates by removing the degrees of freedom that need to be constrained. Thus, the internal coordinate MD (ICMD) offers an attractive alternative to Cartesian coordinate MD for developing multiscale MD method. The torsional MD method is a special adaptation of the ICMD method, where all the bond lengths and bond angles are kept rigid. The advantages of ICMD simulation methods are the longer time step size afforded by freezing high frequency degrees of freedom and performing a conformational search in the more important low frequency torsional degrees of freedom. However, the advancements in the ICMD simulations have been slow and stifled by long-standing mathematical bottlenecks. In this review, we summarize the recent mathematical advancements we have made based on spatial operator algebra, in developing a robust long time scale ICMD simulation toolkit useful for various applications. We also present the applications of ICMD simulations to study conformational changes in proteins and protein structure refinement. We review the advantages of the ICMD simulations over the Cartesian simulations when used with enhanced sampling methods and project the future use of ICMD simulations in protein dynamics.
| S-EPMC4315417 | biostudies-literature
Project description:The first events of unfolding of secondary structure under load are considered with Molecular Dynamics simulations and Milestoning analysis of a long helix (126 amino acids). The Mean First Passage Time is a non-monotonic function of the applied load with a maximum of 3.6 ns at about 20 pN. Network analysis of the reaction space illustrates the opening and closing of an off-pathway trap that slows unfolding at intermediate load levels. It is illustrated that the nature of the reaction networks changes as a function of load, demonstrating that the process is far from one-dimensional.
| S-EPMC3716791 | biostudies-literature
Project description:The flavoenzyme monomeric sarcosine oxidase (MSOX) catalyzes a complex set of reactions currently lacking a consensus mechanism. A key question that arises in weighing competing mechanistic models of MSOX function is to what extent ingress of O2 from the solvent (and its egress after an unsuccessful oxidation attempt) limits the overall catalytic rate. To address this question, we have applied to the MSOX/O2 system the relatively new simulation method of Markovian milestoning molecular dynamics simulations, which, as we recently showed [ Yu et al. J. Am. Chem. Soc. 2015 , 137 , 3041 ], accurately predicted the entry and exit kinetics of CO in myoglobin. We show that the mechanism of O2 entry and exit, in terms of which possible solvent-to-active-site channels contribute to the flow of O2, is sensitive to the presence of the substrate-mimicking competitive inhibitor 2-furoate in the substrate site. The second-order O2 entry rate constants were computed to be 8.1 × 10(6) and 3.1 × 10(6) M(-1) s(-1) for bound and apo MSOX, respectively, both of which moderately exceed the experimentally determined second-order rate constant of (2.83 ± 0.07) × 10(5) M(-1) s(-1) for flavin oxidation by O2 in MSOX. This suggests that the rate of flavin oxidation by O2 is likely not strongly limited by diffusion from the solvent to the active site. The first-order exit rate constants were computed to be 10(7) s(-1) and 7.2 × 10(6) s(-1) for the apo and bound states, respectively. The predicted faster entry and slower exit of O2 for the bound state indicate a longer residence time within MSOX, increasing the likelihood of collisions with the flavin isoalloxazine ring, a step required for reduction of molecular O2 and subsequent reoxidation of the flavin. This is also indirectly supported by previous experimental evidence favoring the so-called modified ping-pong mechanism, the distinguishing feature of which is an intermediate complex involving O2, the flavin, and the oxidized substrate simultaneously in the cavity. These findings demonstrate the utility of the Markovian milestoning approach in contributing new understanding of complicated enyzmatic function.
| S-EPMC5501303 | biostudies-literature
Project description:Presented is the implementation of the Drude force field in the open-source OpenMM simulation package allowing for access to graphical processing unit (GPU) hardware. In the Drude model, electronic degrees of freedom are represented by negatively charged particles attached to their parent atoms via harmonic springs, such that extra computational overhead comes from these additional particles and virtual sites representing lone pairs on electronegative atoms, as well as the associated thermostat and integration algorithms. This leads to an approximately fourfold increase in computational demand over additive force fields. However, by making the Drude model accessible to consumer-grade desktop GPU hardware it will be possible to perform simulations of one microsecond or more in less than a month, indicating that the barrier to employ polarizable models has largely been removed such that polarizable simulations with the classical Drude model are readily accessible and practical.
| S-EPMC6031474 | biostudies-literature
Project description:Protein functions require specific structures frequently coupled with conformational changes. The scale of the structural dynamics of proteins spans from the atomic to the molecular level. Theoretically, all-atom molecular dynamics (MD) simulation is a powerful tool to investigate protein dynamics because the MD simulation is capable of capturing conformational changes obeying the intrinsically structural features. However, to study long-timescale dynamics, efficient sampling techniques and coarse-grained (CG) approaches coupled with all-atom MD simulations, termed multiscale MD simulations, are required to overcome the timescale limitation in all-atom MD simulations. Here, we review two examples of rotary motor proteins examined using free energy landscape (FEL) analysis and CG-MD simulations. In the FEL analysis, FEL is calculated as a function of reaction coordinates, and the long-timescale dynamics corresponding to conformational changes is described as transitions on the FEL surface. Another approach is the utilization of the CG model, in which the CG parameters are tuned using the fluctuation matching methodology with all-atom MD simulations. The long-timespan dynamics is then elucidated straightforwardly by using CG-MD simulations.
| S-EPMC5899732 | biostudies-literature
Project description:When photoactive molecules interact strongly with confined light modes in optical cavities, new hybrid light-matter states form. They are known as polaritons and correspond to coherent superpositions of excitations of the molecules and of the cavity photon. The polariton energies and thus potential energy surfaces are changed with respect to the bare molecules, such that polariton formation is considered a promising paradigm for controlling photochemical reactions. To effectively manipulate photochemistry with confined light, the molecules need to remain in the polaritonic state long enough for the reaction on the modified potential energy surface to take place. To understand what determines this lifetime, we have performed atomistic molecular dynamics simulations of room-temperature ensembles of rhodamine chromophores strongly coupled to a single confined light mode with a 15 fs lifetime. We investigated three popular experimental scenarios and followed the relaxation after optically pumping (i) the lower polariton, (ii) the upper polariton, or (iii) uncoupled molecular states. The results of the simulations suggest that the lifetimes of the optically accessible lower and upper polaritons are limited by (i) ultrafast photoemission due to the low cavity lifetime and (ii) reversible population transfer into the "dark" state manifold. Dark states are superpositions of molecular excitations but with much smaller contributions from the cavity photon, decreasing their emission rates and hence increasing their lifetimes. We find that population transfer between polaritonic modes and dark states is determined by the overlap between the polaritonic and molecular absorption spectra. Importantly, excitation can also be transferred "upward" from the lower polariton into the dark-state reservoir due to the broad absorption spectra of the chromophores, contrary to the common conception of these processes as a "one-way" relaxation from the dark states down to the lower polariton. Our results thus suggest that polaritonic chemistry relying on modified dynamics taking place within the lower polariton manifold requires cavities with sufficiently long lifetimes and, at the same time, strong light-matter coupling strengths to prevent the back-transfer of excitation into the dark states.
| S-EPMC6914212 | biostudies-literature