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Computational Research in Molecular Chemistry
The Dynamic Picture of Protein StructureJ. Andrew McCammon and Martin KarplusAccounts of Chemical Research, Vol. 16, Issue 6, pp. 187-193 (1983, Invited review)    
An important change is occurring in our picture of globular proteins. These molecules have traditionally been described in static terms. The high specificity of enzymes for their substrates has, for example, been likened to the complementarity of two pieces of a jigsaw puzzle. The static view of protein structure is now being replaced by a dynamic picture. It is recognized that the protein atoms are in a state of constant motion. The average positions correspond to what may be seen in an X-ray structure, but the atoms exhibit fluidlike motions of sizable amplitude around these average positions. The new dynamic picture subsumes the static picture in that the average positions allow for interpretation of many aspects of protein function in the classical language of structural chemistry. The recognition of the importance of fluctuations opens the way for more sophisticated and accurate discussions of protein function.
Generalized Langevin Dynamics Simulations with Arbitrary Time-Dependent Memory KernelsM. Berkowitz, J.D. Morgan and J.A. McCammonJournal of Chemical Physics, Vol. 78, Issue 6, pp. 3256-3261 (1983)    
An algorithm is described that allows dynamical simulations to be performed based on generalized Langevin equations with arbitrary, time-dependent memory kernels. Test simulations show that good results are obtained for kernels with distinctly different forms (e.g., exponential and Gaussian).
Molecular Dynamics of Ferrocytochrome c: Time Dependence of the Atomic DisplacementsJohn D. Morgan, J. Andrew McCammon and Scott H. NorthrupBiopolymers, Vol. 22, Issue 6, pp. 1579-1593 (1983)    
The thermal motions of the atoms in a dynamical simulation of ferrocytochrome c are geometrically decomposed into local and highly collective components, and the contributions of these components to the net motion are determined for different intervals of time. It is found that the atomic displacement magnitudes and anisotropies are governed by local motions for times < 10-12s, but that the highly collective motions tend to be dominant at longer times. Variations in this behavior are noted among different groups of atoms. Orientational correlations between the preferred directions of atomic displacement and elements of the protein structure are analyzed as a function of time scale. Finally, several sinificant implications of these results with respect to protein structure and function are considered.
Protein DynamicsJ.A. McCammon and B. MaoMcGraw-Hill Yearbook of Science and Technology, 1984 (Supplement to Encyclopedia of Science and Technology, 5th Ed.), pp. 363-365 (1983, Invited review)    
Dynamics of Proteins: Elements and FunctionM. Karplus and J.A. McCammonAnnual Review of Biochemistry, Vol. 52, No. 1, pp. 263-300 (1983, Invited review)    [PubMed 6351724]
The classic view of proteins has been static in character, primarily because of the dominant role of the information provided by high-resolution X-ray crystallography for these very complex systems. The intrinsic beauty and remarkable detail of the drawings of protein structures led to an image in which each protein atom is fixed in place; an article on lysozyme by Phillips , the books by Dickerson & Geis, and by Perutz & Fermi, the review by Richardson give striking examples. Stating clearly the static viewpoint, Tanford suggested that as a result of packing considerations "the structure of native proteins must be quite rigid." Phillips wrote recently "... the period 1965-75 may be described as the decade of the rigid macromolecule. Brass models of double helical DNA and a variety of protein molecules dominated the scene and much of the thinking."
Side-Chain Rotational Isomerization in Proteins: A Mechanism Involving Gating and Transient Packing DefectsJ.A. McCammon, C.Y. Lee and S.H. NorthrupJournal of the American Chemical Society, Vol. 105, Issue 8, pp. 2232-2237 (1983)    
Tyrosine ring rotational isomerization trajectories from a dynamical simulation are analyzed to clarify the involvement of structural fluctuations in the surrounding protein matrix. The correlation of matrix atom displacements with ring rotation is determined by examination of both ensemble averages and time sequences of protein configurations. Transient packing defects are quantitatively assessed by the Voronoi polyhedron method. The results show that the isomerization is a gated process, in which the ring rotation is systematically preceded by the spontaneous displacement of a section of adjacent backbone. This displacement creates a transient packing defect (~ 10 Å3) that helps to initiate the transition and reduces the energy barrier for the transition proper by relieving unfavorable van der Waals contacts. The results are discussed in the context of current models for motion in proteins, liquids, and solids.
Diffusion-Controlled Reactions: A Variational Formula for the Optimum Reaction CoordinateMax Berkowitz, J.D. Morgan, J.A. McCammon and S.H. NorthrupJournal of Chemical Physics, Vol. 79, Issue 11, pp. 5563-5565 (1983)    
The preferred path for a diffusion-controlled reaction depends, in general, upon global properties of the potential surface and the frictional resistance to motion upon this surface. A variational formula for this path is derived. The corresponding Euler-Lagrange equations are examined for two important special cases.
Theoretical Study of Hinge-bending in L-Arabinose-Binding Protein: Internal Energy and Free Energy ChangesBoryeu Mao and J. Andrew McCammonJournal of Biological Chemistry, Vol. 258, Issue 20, pp. 12543-12547 (1983)    [PubMed 6355087]
The L-arabinose-binding protein of Escherichia coli is a periplasmic component of the L-arabinose transport system. Its three-dimensional structure has been determined by x-ray diffraction and shown to have two globular domains and a connecting hinge. These structural features enclose a cleft in which the L-arabinose-binding site is located. The flexibility of the protein hinge that allows hinge-bending motion is investigated here by theoretical analysis of the changes in conformational energy and molecular structure that accompany the opening and closing of the cleft. The hinge of the molecule is found to be quite permissive in that only moderate increases in the internal energy occur upon opening the cleft. Solvation changes of charged groups on the cleft-facing surfaces of the lobes are estimated to make important contributions to the overall energetics of the system. The results indicate that an open conformation for the unliganded protein is stabilized by the exposure and solvation of charged groups in the cleft, and that the cleft is induced to close upon ligand binding. This picture is consistent with experimental data on the structure and the binding kinetics of L-arabinose-binding protein, and provides a physical framework for interpreting such data.
Saddle-Point Avoidance in Diffusional ReactionsScott H. Northrup and J. Andrew McCammonJournal of Chemical Physics, Vol. 78, Issue 2, pp. 987-989 (1983)    
An important concept in chemical reactions is the reaction coordinate. The identification of a preferred reaction pathway on a multidimensional energy surface is essential both for definition of the mechanism and efficient calculation of the rate of a reaction. In certain cases, such as the rotational isomerization of polymers in solution, one encounters heavily damped diffusive motion on soft potential surfaces. The identification of reaction paths in such cases requires consideration not only of the potential energy surface, but also of the inherent diffusion-preferred motion. In an important recent paper, van der Zwan and Hynes correctly identified the preferred direction of motion through a saddle point as the direction minimizing the work done against both potential and frictional forces. In this communication, we point out that cases can occur in which frictional effects cause the preferred reaction pathway to bypass saddle points completely. We also show that such cases can be analyzed approximately by contracted models of the reaction kinetics.
Molecular Dynamics of Phenylalanine Transfer RNAM. Prabhakaran, S.C. Harvey, B. Mao and J.A. McCammonJournal of Biomolecular Structure and Dynamics, Vol. 1, pp. 357-369 (1983)    [PubMed 6401115]
The atomic motions of yeast phenylalanine transfer RNA have been simulated using the molecular dynamics algorithm. Two simulations were carried out for a period of 12 picoseconds, one with a normal Van der Waals potential and the other with a modified Van der Waals potential intended to mimic the effect of solvent. An analysis of large scale motions, surface exposure, root mean square displacements, helical oscillations and relaxation mechanisms reveals the maintenance of stability in the simulated structures and the general similarity of the various dynamic features of the two simulations. The regions of conformational flexibility and rigidity for tRNA(Phe) have been shown in a quantitative measure through this approach.
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