Scott H. Northrup

Bio: Scott H. Northrup is an academic researcher from Tennessee Technological University. The author has contributed to research in topics: Brownian dynamics & Cytochrome c peroxidase. The author has an hindex of 32, co-authored 64 publications receiving 4021 citations. Previous affiliations of Scott H. Northrup include University of Houston & University of North Dakota.

Kinetics of protein-protein association explained by Brownian dynamics computer simulation.

Abstract: Protein-protein bond formations, such as antibody-antigen complexation or aggregation of protein monomers into dimers and larger aggregates, occur with bimolecular rate constants on the order of 10(6) M-1.s-1, which is only 3 orders of magnitude slower than the diffusion-limited Smoluchowski rate. However, since the protein-protein bond requires rotational alignment to within a few angstroms of tolerance, purely geometric estimates would suggest that the observed rates might be 6 orders of magnitude below the Smoluchowski rate. Previous theoretical treatments have not been solved for the highly specific docking criteria of protein-protein association--the entire subunit interface must be aligned within 2 A of the correct position. Several studies have suggested that diffusion alone could not produce the rapid association kinetics and have postulated "lengthy collisions" and/or the operation of electrostatic or hydrophobic steering forces to accelerate the association. In the present study, the Brownian dynamics simulation method is used to compute the rate of association of neutral spherical model proteins with the stated docking criteria. The Brownian simulation predicts a rate of 2 x 10(6) M-1.s-1 for this generic protein-protein association, a rate that is 2000 times faster than that predicted by the simplest geometric calculation and is essentially equal to the rates observed for protein-protein association in aqueous solution. This high rate is obtained by simple diffusive processes and does not require any attractive or steering forces beyond those achieved for a partially formed bond. The rate enhancement is attributed to a diffusive entrapment effect, in which a protein pair surrounded and trapped by water undergoes multiple collisions with rotational reorientation during each encounter.

Brownian dynamics simulation of diffusion‐influenced bimolecular reactions

Abstract: A method is developed and tested for extracting diffusion‐controlled rate constants for condensed phase bimolecular reactions from Brownian dynamics trajectory simulations. This method will be useful when highly detailed model systems are employed, such as those required to explore the complicated range of interactions between enzymes and their substrates. The method is verified by comparing with exact analytical results for simple cases of spheres with uniform reactivity subject to various centrosymmetric Coulombic and Oseen slip hydrodynamic interactions. The utility of the method is illustrated for more complicated cases involving anisotropic reactivity and rotational diffusion.

Brownian dynamics of cytochrome c and cytochrome c peroxidase association.

Abstract: Brownian dynamics computer simulations of the diffusional association of electron transport proteins cytochrome c (cyt c) and cytochrome c peroxidase (cyt c per) were performed. A highly detailed and realistic model of the protein structures and their electrostatic interactions was used that was based on an atomic-level spatial description. Several structural features played a role in enhancing and optimizing the electron transfer efficiency of this reaction. Favorable electrostatic interactions facilitated long-lived nonspecific encounters between the proteins that allowed the severe orientational criteria for reaction to be overcome by rotational diffusion during encounters. Thus a "reduction-in-dimensionality" effect operated. The proteins achieved plausible electron transfer orientations in a multitude of electrostatically stable encounter complexes, rather than in a single dominant complex.

The stable states picture of chemical reactions. I. Formulation for rate constants and initial condition effects

Abstract: The stable states picture (SSP) of chemical reactions is used to derive flux time correlation function (tcf) formulas for reaction rate constants. These formulas, which apply to both gas phase and condensed phase reactions, are interpreted in terms of the flux out of an internally equilibrated stable reactant and the ensuing irreversible flux into a stable product. The determination of the rate constants by dynamics in an intermediate region lying between these stable states is illustrated for a simple model of barrier crossing in liquids. Generalized rate constant expressions which hold when internal nonequilibrium in the stable states is important are derived and discussed. The SSP approach is also used to derive tcf expressions for short time initial condition effects which carry information on reactive dynamics beyond that contained in rate constants. As an illustration, it is shown how the SSP formulation provides a starting point for the resolution of primary and secondary recombination in liquid state photodissociation reactions.

Stochastically gated diffusion‐influenced reactions

Abstract: The theory of diffusion‐influenced reactions is extended to cases where the reactivity of the species fluctuates in time (e.g., the accessibility of a binding site of a protein is modulated by a gate). The opening and closing of the gate is assumed to be a stationary Markov process [i.e., it is described by the kinetic scheme (open) a⇄b (closed)]. When the reaction is described by suitable boundary conditions, by solving the appropriate reaction‐diffusion equations, it is shown that the stochastically gated association rate constant (kSG) is given by k−1SG=k−1∞ + [a−1 b(a+b)κu(a+b)]−1, where κu(s) is the Laplace transform of the time‐dependent rate constant of the ungated problem and k∞ is the corresponding steady‐state rate constant. The limits when the relaxation time for gate fluctuations is larger or smaller than the characteristic time for diffusion are considered. The relation to previous work is discussed. The theory is applied to three models: (i) a gated sphere, (ii) a gated disk on an infinite plane (e.g., a channel in a membrane), and (iii) a gated localized axially symmetric reactive site on the surface of a spherical macromolecule.

CHARMM: the biomolecular simulation program.

Abstract: CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecu- lar simulation program. It has been developed over the last three decades with a primary focus on molecules of bio- logical interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estima- tors, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numer- ous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.

Reaction-rate theory: fifty years after Kramers

Abstract: The calculation of rate coefficients is a discipline of nonlinear science of importance to much of physics, chemistry, engineering, and biology. Fifty years after Kramers' seminal paper on thermally activated barrier crossing, the authors report, extend, and interpret much of our current understanding relating to theories of noise-activated escape, for which many of the notable contributions are originating from the communities both of physics and of physical chemistry. Theoretical as well as numerical approaches are discussed for single- and many-dimensional metastable systems (including fields) in gases and condensed phases. The role of many-dimensional transition-state theory is contrasted with Kramers' reaction-rate theory for moderate-to-strong friction; the authors emphasize the physical situation and the close connection between unimolecular rate theory and Kramers' work for weakly damped systems. The rate theory accounting for memory friction is presented, together with a unifying theoretical approach which covers the whole regime of weak-to-moderate-to-strong friction on the same basis (turnover theory). The peculiarities of noise-activated escape in a variety of physically different metastable potential configurations is elucidated in terms of the mean-first-passage-time technique. Moreover, the role and the complexity of escape in driven systems exhibiting possibly multiple, metastable stationary nonequilibrium states is identified. At lower temperatures, quantum tunneling effects start to dominate the rate mechanism. The early quantum approaches as well as the latest quantum versions of Kramers' theory are discussed, thereby providing a description of dissipative escape events at all temperatures. In addition, an attempt is made to discuss prominent experimental work as it relates to Kramers' reaction-rate theory and to indicate the most important areas for future research in theory and experiment.

How Fast-Folding Proteins Fold

Abstract: An outstanding challenge in the field of molecular biology has been to understand the process by which proteins fold into their characteristic three-dimensional structures. Here, we report the results of atomic-level molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally diverse proteins. In simulations conducted with a single physics-based energy function, the proteins, representing all three major structural classes, spontaneously and repeatedly fold to their experimentally determined native structures. Early in the folding process, the protein backbone adopts a nativelike topology while certain secondary structure elements and a small number of nonlocal contacts form. In most cases, folding follows a single dominant route in which elements of the native structure appear in an order highly correlated with their propensity to form in the unfolded state.

Turns in peptides and proteins.

Abstract: Publisher Summary Turns are a fundamental class of polypeptide structure and are defined as sites where the peptide chain reverses its overall direction. In the past 20 years, the peptide field has witnessed major development, stimulated by the discovery of a host of bioactive peptides. Turn structures have been proposed and implicated in the bioactivity of several of these naturally occurring peptides. In addition, many structural details of turns have been derived from conformational studies of model peptides. During this same period, more than 100 complete protein structures have been elucidated in single-crystal X-ray studies. These examples document the rich diversity of structural patterns in the chain folds of native proteins. Turns are intrinsically polar structures with backbone groups that pack together closely and side chains that project outward. Such an array of atoms may constitute a site for molecular recognition, and indeed, the literature abounds with suggestions that turns serve as loci for receptor binding, antibody recognition, and post-translational modification. In peptides, turns are the conformations of choice for simultaneously optimizing both backbone–chain compactness (intramolecular nonbonded contacts) and side-chain clustering (to facilitate intermolecular recognition). Presence of turns in bioactive conformations may in fact also reflect the lack of alternative conformational possibilities. The aim of this chapter is to examine structural and functional roles of turns in peptides and proteins.