Computer Simulation Study of the Binding of an Antiviral Agent to a Sensitive and a Resistant Human RhinovirusTerry P. Lybrand and J. Andrew McCammonJournal of Computer-Aided Molecular Design, Vol. 2, No. 4, pp. 259-266 (1989) [PubMed 2541225]Molecular dynamics simulations have been used to study the free energy
of binding of an antiviral agent to the human rhinovirus HRV-14 and to a
mutant in which a valine residue in the antiviral binding pocket is
replaced by leucine. The simulations predict that the antiviral should
bind to the two viruses with similar affinity, in apparent disagreement
with experimental results. Possible origins of this discrepancy are
outlined. Of particular importance is the apparent need for methods to
systematically sample all significant conformations of the leucine side
chain.
Diffusion-Controlled Reactions of Ions in Fluctuating Ionic AtmospheresS. Sridharan, J.A. McCammon and J.B. HubbardJournal of Chemical Physics, Vol. 90, Issue 1, pp. 237-240 (1989)
The effects of co- and counterion dynamics on the rates of diffusion
controlled reactions are investigated. A model system consisting of
univalent soft spheres in a uniform dielectric medium is simulated by
the Brownian dynamics method. This system is used to study the effects
of ionic atmosphere dynamics on the rate of recombination of an ion
pair. The results show a small (2%) increase in the rate compared to the
traditional Debye-Hückel description. A parallel calculation where
the atmospheric ions are frozen in equilibrium configurations around the
target (unperturbed by the incoming reactant) yields results which are
very close to the Debye-Hückel results. Larger nonequilibrium
effects are expected for multivalent electrolytes.
Molecular Recognition in Nonaqueous Solvents: Na+, K+, and 18-crown-6 in MethanolMichael H. Mazor, J. Andrew McCammon and Terry P. LybrandJournal of the American Chemical Society, Vol. 111, Issue 1, pp. 55-56 (1989)
Molecular dynamic simulations are used to predict the binding affinity
in host-guest systems by the thermodynamic cycle-perturbation method.
The relative free energy of solvation of Na+ and
K+ in methanol (19.6 kcal/mol) and the relative free energy
of binding of Na+ and K+ to 18-crown-6 in methanol
(-3.5 kcal/mol) are calculated by thermodynamic integration in the
canonical ensemble. These results are in reasonable agreement with the
experimental values, 17.3 and -2.47 kcal/mol, respectively.
Methods for Calculating Geometries of Transition States in SolutionJeffry D. Madura, B. Montgomery Pettitt and J. Andrew McCammonChemical Physics, Vol. 129, Issue 2, pp. 185-191 (1989)
Several methods are proposed for determining the differences in
structure and free energy for homologous transition states in a
condensed phase. The first of these methods is based upon the well-known
simplex optimization scheme. The second is a variant of the simplex
method. The third method uses first and second derivatives of the free
energy with respect to the molecular composition and the reaction
coordinate. Free energy difference calculations are used on a simple
model reaction in a Lennard-Jones liquid to display the problem of
finding condensed phase transition states and to test the proposed
algorithms.
Polarizable Water Models: Vectorization of Energy Calculations on the CYBER 205J.C. Sauniere, T.P. Lybrand, J.A. McCammon and L.D. PyleComputers & Chemistry, Vol. 13, Issue 4, pp. 313-317 (1989)
A large fraction of the time spent calculating the energy of a
configuration of polarizable water molecules is spent calculating the
electric field and polarization energy. This paper describes
vectorization strategies for such calculations on the CYBER 205. For a
cluster of 215 waters and the Lybrand-Kollman model, the vectorized
calculation on the CYBER 205 executes at about 47 times VAX 8650 speed,
or about 300 times VAX 11/780 speed.
Solving the Finite Difference Linearized Poisson-Boltzmann Equation: A Comparison of Relaxation and Conjugate Gradient MethodsM.E. Davis and J.A. McCammonJournal of Computational Chemistry, Vol. 10, Issue 3, pp. 386-391 (1989)
Comparisons have been made between relaxation methods and certain
preconditioned conjugate gradient techniques for solving the system of
linear equations arising from the finite-difference form of the
linearized Poisson-Boltzmann equation. The incomplete Cholesky conjugate
gradient (ICCG) method of Meijerink and van der Vorst has been found to
be superior to relaxation methods, with at least a factor of two
improvement in speed, and only a 50% increase in storage.
Treatment of Rotational Isomers in Free Energy Evaluations. Analysis of the Evaluation of Free Energy Differences by Molecular Dynamics Simulations of Systems with Rotational Isomeric StatesT.P. Straatsma and J.A. McCammonJournal of Chemical Physics, Vol. 90, Issue 6, pp. 3300-3304 (1989)
Using 1,2-dimethoxy ethane in aqueous solution as an example, the
applicability of the perturbation method and the thermodynamic
integration technique to evaluate free energy differences is considered
for systems with multiple rotational isomeric states. It is shown that
the naive application of these methods to evaluate free energy
differences for such systems, even in a simple case such as the free
energy of hydration of 1,2-dimethoxy ethane, may lead to unreasonable
results. This problem is due to the fact that, in a conventional
simulation, it is unlikely that all isomeric states will be sampled with
the appropriate equilibrium probabilities. A procedure is proposed to
estimate the contributions of isomeric states in free energy difference
calculations.
Glass Transition in SPC/E Water and in a Protein Solution: A Molecular Dynamics Simulation StudyC.F. Wong, C. Zheng and J.A. McCammonChemical Physics Letters, Vol. 154, pp. 151-154 (1989)
Molecular dynamic simulations of glass transitions in SPC/E water and
tuna ferrocytochrome c solution have been performed. The results support
the suggestion that glass transitions in proteins are driven by those in
the surrounding solvent.
Molecular RecognitionS. Subramaniam and J.A. McCammonNone
How Electrolyte Shielding Influences the Electrical Potential in Transmembrane Ion ChannelsPeter C. Jordan, Russell J. Bacquet, J. Andrew McCammon and Phouc TranBiophysical Journal, Vol. 55, No. 6, pp. 1041-1052 (1989) [PubMed 2475181]The electrical potential due to fixed charge distributions is strongly
altered in the vicinity of a membrane and notably dependent on aqueous
electrolyte concentration. We present an efficient way to solve the
nonlinear Poisson-Boltzmann equation applicable to general cylindrically
symmetric dielectric geometries. It generalizes Gouy-Chapman theory to
systems containing transmembrane channels. The method is applied to
three channel systems: gramicidin, gap junction, and porin. We find that
for a long, narrow channel such as gramicidin concentration variation
has little influence on the electrical image barrier to ion permeation.
However, electrolyte shielding reduces the image induced contribution to
the energy required for multiple occupancy. In addition, the presence of
electrolyte significantly affects the voltage profile due to an applied
potential, substantially compressing the electric field to the immediate
vicinity of the pore itself. In the large diameter channels, where bulk
electrolyte may be assumed to enter the pore, the electrolyte greatly
reduces the image barrier to ion permeation. At physiological ionic
strengths this barrier is negligible and the channel may be readily
multiply occupied. At all ionic strengths considered (l greater than
0.005 M) the image barrier saturates rapidly and is essentially constant
more than one channel radius from the entrance to the pore. At lower
ionic strengths (l less than 0.016 M) there are noticeable (greater than
20 mV) energy penalties associated with multiple occupancy.
Probing Molecular Recognition Using Simulation MethodsS. Subramaniam, J.A. McCammon and R.J. BacquetIn "The Immune Response to Structurally Defined Proteins: The Lysozyme Model," S.J. Smith-Gill and E. Sercarz, Eds., Adenine Press, pp. 169-176 (1989)
Protein Stability and Function: Theoretical StudiesJ.A. McCammon, C.F. Wong and T.P. LybrandIn "Prediction of Protein Structure and the Principles of Protein Conformation," G.D. Fasman, Ed., Plenum, New York, pp. 149-159 (1989)
Superoxide Dismutase: Fluctuations in the Structure and Solvation of the Active Site Channel Studied by Molecular Dynamics SimulationJian Shen, Shankar Subramaniam, Chung F. Wong and J. Andrew McCammonBiopolymers, Vol. 28, Issue 12, pp. 2085-2096 (1989) [PubMed 2605312]The molecular dynamics (MD) simulation of superoxide dismutase (SOD) in
water is carried out for a total of 23 ps. The simulation system is a 26
Angstrom sphere centered at the active site of SOD, including 1602 atoms
from SOD and 1761 water molecules. There is no gross deviation from the
x-ray structure for the average MD structure. The structure and
potential fluctuations around the active site are examined. The results
provide new insight to the interactions between SOD and its substrate
superoxide.
Water and Polypeptide Conformations in Gramicidin Channel - A Molecular Dynamics StudySee-Wing Chiu, Shankar Subramaniam, Eric Jakobsson and J. Andrew McCammonBiophysical Journal, Vol. 56, No. 2, pp. 253-261 (1989) [PubMed 2476188]Theoretical studies of ion channels address several important questions.
The mechanism of ion transport, the role of water structure, the
fluctuations of the protein channel itself, and the influence of
structural changes are accessible from these studies. In this paper, we
have carried out a 70-ps molecular dynamics simulation on a model
structure of gramicidin A with channel waters. The backbone of the
protein has been analyzed with respect to the orientation of the
carbonyl and the amide groups. The results are in conformity with the
experimental NMR data. The structure of water and the hydrogen bonding
network are also investigated. It is found that the water molecules
inside the channel act as a collective chain; whereas the conformation
in which all the waters are oriented with the dipoles pointing along the
axis of the channel is a preferred one, others are also accessed during
the dynamics simulation. A collective coordinate involving the channel
waters and some of the hydrogen bonding peptide partners is required to
describe the transition of waters from one configuration to the other.
Molecular Dynamics Simulation of Protein Hydration: Studies on Tuna Ferrocytochrome-c and Bovine Erythrocyte Superoxide DismutaseC.F. Wong, J. Shen, C. Zheng, S. Subramaniam and J.A. McCammonJournal of Molecular Liquids, Vol. 41, pp. 193-206 (1989, Special issue in honor of G. Careri)
Classical and Quantum Aspects of Ferrocytochrome-cC. Zheng, C.F. Wong, J.A. McCammon and P.G. WolynesChemica Scripta, Vol. 29A, pp. 171-179 (1989, Proceedings of Nobel Symposium)
Treatment of Rotational Isomers in Free Energy Calculations. II. Molecular Dynamics Simulation Study of 18-crown-6 in Aqueous Solution as an Example of Systems with Large Numbers of Rotational Isomeric StatesT.P. Straatsma and J.A. McCammonJournal of Chemical Physics, Vol. 91, Issue 6, pp. 3631-3637 (1989)
The evaluation of free energy differences using the perturbation method
or thermodynamic integration method requires special caution if multiple
rotational isomeric states may exist in the system under investigation.
In this article a recently suggested procedure to properly treat
rotational isomeric states is illustrated with a molecular dynamics
simulation of an aqueous solution of uncomplexed 18-crown-6 crown ether,
as an example of a system in which large numbers of isomeric states may
exist. By using very long molecular dynamics simulations, thermodynamic
perturbation methods and symmetry arguments, the free energy of host
organization into the conformation required to form the complex with
K+ is estimated to be 2.6 kJ/mol. It has also been found that
the lowest energy conformations of 18-crown-6 in vacuo do not
necessarily correspond to the most populated conformations in aqueous
solution.
Quantum Simulation of Nuclear Rearrangement in Electron Transfer ReactionsChong Zheng, J. Andrew McCammon and Peter G. WolynesProceedings of the National Academy of Sciences of the USA, Vol. 86, No. 17, pp. 6441-6444 (1989) [PubMed 16594063]A quantum simulation scheme based on the path integral molecular
dynamics technique has been used to calculate the effective activation
energies associated with nuclear rearrangement in the electron transfer
reactions Co(NH
3)
62+ +
Co(NH
3)
63+ →
Co(NH
3)
63+ +
Co(NH
3)
62+ and
Ru(NH
3)
62+ +
Ru(NH
3)
63+ →
Ru(NH
3)
63+ +
Ru(NH
3)
62+. Even with a simple
Hamiltonian and short time dynamic simulations, the results are in
satisfactory agreement with other theoretical calculations. This
simulation approach can be used in chemical and biological systems where
the reactions are largely controlled by nuclear rearrangements, such as
those of electron transfer reactions in some electron carrier proteins.
Brownian Dynamics Simulation of Diffusional Encounters Between Triose Phosphate Isomerase and D-Glyceraldehyde PhosphateJeffry D. Madura and J. Andrew McCammonJournal of Physical Chemistry, Vol. 93, No. 21, pp. 7285-7287 (1989)
A preliminary estimate of the diffusion-controlled rate constant has
been calculated for chicken muscle triose phosphate isomerase (TIM) with
D-glyceraldehydephosphate (GAP) by the method of Brownian dynamics. The
crystal structure was used in constructing a detailed topographical and
electrostatic model of the dimeric enzyme. Two simulations were done,
one without and the other with electrostatic interactions between the
enzyme and substrate. The resulting rate constants were calculated to be
3.1 x 109 and 1.5 x 1010 (M s)-1,
respectively. Both rate constants are larger than the experimental value
of 4.8 x 108 (M s)-1. These results suggest that
electrostatic steering of substrate contributes to the high rate
constant for the enzyme but that several features must be added to the
current simulation model to yield fully satisfactory agreement with
experiments.