Add support for computing dG gradient w.r.t solvent params (#121)

smee/mm/_fe.py

@@ -24,6 +24,30 @@
 _NM_TO_ANGSTROM = 10.0
 
 
+def _extract_pure_solvent(
+    force_field: smee.TensorForceField, output_dir: pathlib.Path
+) -> tuple[smee.TensorSystem, torch.Tensor, torch.Tensor, float, float, torch.Tensor]:
+    device = force_field.potentials[0].parameters.device
+    dtype = force_field.potentials[0].parameters.dtype
+
+    system, beta, pressure, u_kn, n_k, xyz, box = _load_samples(
+        output_dir, device, dtype, coord_state_idx=-1
+    )
+
+    if len(system.topologies) != 2 or system.n_copies[0] != 1:
+        raise NotImplementedError("only single solute systems are supported.")
+
+    n_solute_atoms = system.topologies[0].n_atoms
+    xyz = xyz[:, n_solute_atoms:, :]
+
+    system = smee.TensorSystem(
+        [system.topologies[1]], [system.n_copies[1]], is_periodic=True
+    )
+    energy = _compute_energy(system, force_field, xyz, box)
+
+    return system, xyz, box, beta, pressure, energy
+
+
 def generate_dg_solv_data(
     solute: smee.TensorTopology,
     solvent: smee.TensorTopology,
@@ -145,10 +169,15 @@ def _parameterize(
         parmed.openmm.load_topology(prepared_system_a.topology.to_openmm()),
     )
 
-    return absolv.runner.run_eq(
+    result = absolv.runner.run_eq(
         config, prepared_system_a, prepared_system_b, "CUDA", output_dir, parallel=True
     )
 
+    solvent_b_output = _extract_pure_solvent(force_field, output_dir / "solvent-b")
+    torch.save(solvent_b_output, output_dir / "solvent-b" / "pure.pt")
+
+    return result
+
 
 def _uncorrelated_frames(length: int, g: float) -> list[int]:
     """Return the indices of frames that are un-correlated.
@@ -214,7 +243,10 @@ def _load_trajectory(
 
 
 def _load_samples(
-    output_dir: pathlib.Path, device: str | torch.device, dtype: torch.dtype
+    output_dir: pathlib.Path,
+    device: str | torch.device,
+    dtype: torch.dtype,
+    coord_state_idx: int = 0,
 ) -> tuple[
     smee.TensorSystem,
     float,
@@ -256,10 +288,6 @@ def _load_samples(
     u_kn = numpy.hstack([numpy.array(x) for x in output_table["u_kn"].to_pylist()])
     u_kn_per_k = [u_kn[:, replica_to_state_idx == i] for i in range(len(u_kn))]
 
-    xyz_0, box_0 = _load_trajectory(
-        output_dir / "trajectories", system, replica_to_state_idx
-    )
-
     n_uncorrelated = u_kn.shape[1] // u_kn.shape[0]
 
     g = pymbar.timeseries.statistical_inefficiency_multiple(
@@ -270,9 +298,6 @@ def _load_samples(
     )
     uncorrelated_frames = _uncorrelated_frames(n_uncorrelated, g)
 
-    xyz_0 = xyz_0[uncorrelated_frames]
-    box_0 = box_0[uncorrelated_frames] if box_0 is not None else None
-
     for state_idx, state_u_kn in enumerate(u_kn_per_k):
         u_kn_per_k[state_idx] = state_u_kn[:, uncorrelated_frames]
 
@@ -281,17 +306,25 @@ def _load_samples(
 
     n_expected_frames = int(u_kn.shape[1] // len(u_kn))
 
-    assert len(xyz_0) == n_expected_frames
-    assert box_0 is None or len(box_0) == n_expected_frames
+    if coord_state_idx < 0:
+        coord_state_idx = len(u_kn) + coord_state_idx
+
+    xyz_i, box_i = _load_trajectory(
+        output_dir / "trajectories", system, replica_to_state_idx, coord_state_idx
+    )
+    xyz_i = xyz_i[uncorrelated_frames]
+    box_i = box_i[uncorrelated_frames] if box_i is not None else None
+    assert len(xyz_i) == n_expected_frames
+    assert box_i is None or len(box_i) == n_expected_frames
 
     return (
         system.to(device),
         beta,
         pressure,
         torch.tensor(u_kn, device=device, dtype=dtype),
         torch.tensor(n_k, device=device),
-        torch.tensor(xyz_0, device=device, dtype=dtype),
-        torch.tensor(box_0, device=device, dtype=dtype) if box_0 is not None else None,
+        torch.tensor(xyz_i, device=device, dtype=dtype),
+        torch.tensor(box_i, device=device, dtype=dtype) if box_i is not None else None,
     )
 
 
@@ -345,6 +378,26 @@ def compute_dg_and_grads(
     return smee.utils.tensor_like(dg, force_field.potentials[0].parameters), grads
 
 
+def compute_grads_solvent(
+    force_field: smee.TensorForceField,
+    theta: tuple[torch.Tensor, ...],
+    output_dir: pathlib.Path,
+) -> tuple[torch.Tensor, ...]:
+    device = force_field.potentials[0].parameters.device
+
+    system, xyz, box, *_ = torch.load(output_dir / "pure.pt")
+    system.to(device)
+
+    grads = ()
+
+    if len(theta) > 0:
+        with torch.enable_grad():
+            energy = _compute_energy(system, force_field, xyz, box)
+            grads = torch.autograd.grad(energy.mean(), theta)
+
+    return grads
+
+
 def reweight_dg_and_grads(
     force_field: smee.TensorForceField,
     theta: tuple[torch.Tensor, ...],
@@ -392,3 +445,48 @@ def reweight_dg_and_grads(
             grads = torch.autograd.grad((energy_0 * weights).sum(), theta)
 
     return smee.utils.tensor_like(dg, energy_0), grads, n_eff
+
+
+def reweight_grads_solvent(
+    force_field: smee.TensorForceField,
+    theta: tuple[torch.Tensor, ...],
+    output_dir: pathlib.Path,
+) -> tuple[tuple[torch.Tensor, ...], float]:
+    import pymbar
+
+    device = force_field.potentials[0].parameters.device
+
+    system, xyz, box, beta, pressure, energy_old = torch.load(output_dir / "pure.pt")
+    system.to(device)
+
+    u_old = energy_old.detach().clone() * beta
+
+    if pressure is not None:
+        u_old += pressure * torch.det(box) * beta
+
+    with torch.enable_grad():
+        energy_new = _compute_energy(system, force_field, xyz, box)
+
+        u_new = energy_new.detach().clone() * beta
+
+        if pressure is not None:
+            u_new += pressure * torch.det(box) * beta
+
+        u_kn = numpy.stack([u_old.cpu().numpy(), u_new.cpu().numpy()])
+        n_k = numpy.array([len(u_old), 0])
+
+        mbar = pymbar.MBAR(
+            u_kn,
+            n_k,
+            solver_protocol=[{"method": "adaptive", "options": {"min_sc_iter": 0}}],
+        )
+
+        n_eff = mbar.compute_effective_sample_number().min().item()
+
+        weights = smee.utils.tensor_like(mbar.W_nk[:, 1], energy_new)
+        grads = ()
+
+        if len(theta) > 0:
+            grads = torch.autograd.grad((energy_new * weights).sum(), theta)
+
+    return grads, n_eff

smee/mm/_ops.py

@@ -616,7 +616,7 @@ def reweight_ensemble_averages(
 class _ComputeDGSolv(torch.autograd.Function):
     @staticmethod
     def forward(ctx, kwargs, *theta: torch.Tensor):
-        from smee.mm._fe import compute_dg_and_grads
+        from smee.mm._fe import compute_dg_and_grads, compute_grads_solvent
 
         force_field = _unpack_force_field(
             theta,
@@ -638,11 +638,19 @@ def forward(ctx, kwargs, *theta: torch.Tensor):
             force_field, theta_grad, kwargs["fep_dir"] / "solvent-b"
         )
 
+        if (kwargs["fep_dir"] / "solvent-a" / "pure.pt").exists():
+            raise NotImplementedError("solvent-a is expected to be vacuum")
+
+        dg_solv_b_d_theta = compute_grads_solvent(
+            force_field, theta_grad, kwargs["fep_dir"] / "solvent-b"
+        )
+
         dg = dg_a - dg_b
         dg_d_theta = [None] * len(theta)
 
         for grad_idx, orig_idx in enumerate(needs_grad):
             dg_d_theta[orig_idx] = dg_d_theta_b[grad_idx] - dg_d_theta_a[grad_idx]
+            dg_d_theta[orig_idx] -= dg_solv_b_d_theta[grad_idx]
 
         ctx.save_for_backward(*dg_d_theta)
 
@@ -659,7 +667,7 @@ def backward(ctx, *grad_outputs):
 class _ReweightDGSolv(torch.autograd.Function):
     @staticmethod
     def forward(ctx, kwargs, *theta: torch.Tensor):
-        from smee.mm._fe import reweight_dg_and_grads
+        from smee.mm._fe import reweight_dg_and_grads, reweight_grads_solvent
 
         force_field = _unpack_force_field(
             theta,
@@ -684,15 +692,23 @@ def forward(ctx, kwargs, *theta: torch.Tensor):
             force_field, theta_grad, kwargs["fep_dir"] / "solvent-b"
         )
 
+        if (kwargs["fep_dir"] / "solvent-a" / "pure.pt").exists():
+            raise NotImplementedError("solvent-a is expected to be vacuum")
+
+        dg_solv_b_d_theta, n_effective_solv = reweight_grads_solvent(
+            force_field, theta_grad, kwargs["fep_dir"] / "solvent-b"
+        )
+
         dg = -dg_a + dg_0 + dg_b
         dg_d_theta = [None] * len(theta)
 
         for grad_idx, orig_idx in enumerate(needs_grad):
             dg_d_theta[orig_idx] = dg_d_theta_b[grad_idx] - dg_d_theta_a[grad_idx]
+            dg_d_theta[orig_idx] -= dg_solv_b_d_theta[grad_idx]
 
         ctx.save_for_backward(*dg_d_theta)
 
-        return dg, min(n_effective_a, n_effective_b)
+        return dg, min(n_effective_a, n_effective_b, n_effective_solv)
 
     @staticmethod
     def backward(ctx, *grad_outputs):
@@ -708,9 +724,8 @@ def compute_dg_solv(
     """Computes ∆G_solv from existing FEP data.
 
     Notes:
-        Currently the gradient of the pure solvent is not computed. This will mean the
-        gradient w.r.t. water parameters currently will be incorrect when using this
-        to compute hydration free energies.
+        It is assumed that FEP data was generated using the same force field as
+        ``force_field``, and using ``generate_dg_solv_data``
 
     Args:
         force_field: The force field used to generate the FEP data.
@@ -743,9 +758,7 @@ def reweight_dg_solv(
     """Computes ∆G_solv by re-weighting existing FEP data.
 
     Notes:
-        Currently the gradient of the pure solvent is not computed. This will mean the
-        gradient w.r.t. water parameters currently will be incorrect when using this
-        to compute hydration free energies.
+        It is assumed that FEP data was generated using ``generate_dg_solv_data``.
 
     Args:
         force_field: The force field to reweight to.

smee/tests/mm/test_fe.py

@@ -31,21 +31,21 @@ def load_systems(solute: str, solvent: str):
 
 @pytest.mark.fe
 def test_fe_ops(tmp_cwd):
-    # taken from a run on commit 7915d1e323318d2314a8b0322e7f44968c660c21
+    # taken from a run on commit ec3d272b466f761ed838e16a5ba7b97ceadc463b
     expected_dg = torch.tensor(-3.8262).double()
     expected_dg_dtheta = torch.tensor(
         [
-            [1.0288e01],
-            [1.3976e01],
-            [2.6423e01],
-            [9.1453e00],
-            [9.0158e00],
-            [9.5534e00],
-            [1.0414e01],
-            [1.1257e01],
-            [-4.0618e00],
-            [5.0233e03],
-            [-1.3574e03],
+            [10.2679],
+            [13.3933],
+            [25.3670],
+            [9.3747],
+            [9.3279],
+            [9.1520],
+            [10.5614],
+            [9.6908],
+            [-4.4326],
+            [-17.3971],
+            [-38.5407],
         ]
     ).double()
 
@@ -62,11 +62,17 @@ def test_fe_ops(tmp_cwd):
     dg = smee.mm.compute_dg_solv(ff, output_dir)
     dg_dtheta = torch.autograd.grad(dg, params)[0]
 
+    print("dg COMP", dg, flush=True)
+    print("dg_dtheta COMP", dg_dtheta, dg, flush=True)
+
     assert dg == pytest.approx(expected_dg, abs=0.5)
     assert dg_dtheta == pytest.approx(expected_dg_dtheta, rel=1.1)
 
     dg, n_eff = smee.mm.reweight_dg_solv(ff, output_dir, dg)
     dg_dtheta = torch.autograd.grad(dg, params)[0]
 
+    print("dg REWEIGHT", dg, flush=True)
+    print("dg_dtheta REWEIGHT", dg_dtheta, dg, flush=True)
+
     assert dg == pytest.approx(expected_dg, abs=0.5)
     assert dg_dtheta == pytest.approx(expected_dg_dtheta, rel=1.1)

smee/tests/mm/test_ops.py

@@ -448,12 +448,16 @@ def test_compute_dg_solv(mocker, tmp_path, mock_argon_tensors):
             (torch.tensor(4.0).double(), (torch.tensor([[5.0, 6.0]]).double(),)),
         ],
     )
+    mocker.patch(
+        "smee.mm._fe.compute_grads_solvent",
+        side_effect=[(torch.tensor([[8.0, 9.0]]).double(),)],
+    )
 
     dg = smee.mm.compute_dg_solv(tensor_ff, tmp_path)
     dg_dtheta = torch.autograd.grad(dg, params)[0]
 
     assert torch.isclose(dg, torch.tensor(-3.0).double())
-    assert torch.allclose(dg_dtheta, torch.tensor([[3.0, 3.0]]).double())
+    assert torch.allclose(dg_dtheta, torch.tensor([[-5.0, -6.0]]).double())
 
 
 def test_reweight_dg_solv(mocker, tmp_path, mock_argon_tensors):
@@ -469,14 +473,18 @@ def test_reweight_dg_solv(mocker, tmp_path, mock_argon_tensors):
             (torch.tensor(5.0).double(), (torch.tensor([[6.0, 7.0]]).double(),), 8.0),
         ],
     )
+    mocker.patch(
+        "smee.mm._fe.reweight_grads_solvent",
+        side_effect=[((torch.tensor([[9.0, 10.0]]).double(),), 11.0)],
+    )
 
     dg_0 = torch.tensor(-3.0).double()
 
     dg, n_eff = smee.mm.reweight_dg_solv(tensor_ff, tmp_path, dg_0, 3)
     dg_dtheta = torch.autograd.grad(dg, params)[0]
 
     assert torch.isclose(dg, torch.tensor(1.0).double())
-    assert torch.allclose(dg_dtheta, torch.tensor([[4.0, 4.0]]).double())
+    assert torch.allclose(dg_dtheta, torch.tensor([[-5.0, -6.0]]).double())
 
     assert n_eff == 4.0
 
@@ -494,6 +502,11 @@ def test_reweight_dg_solv_error(mocker, tmp_path, mock_argon_tensors):
             (torch.tensor(5.0).double(), (torch.tensor([[6.0, 7.0]]).double(),), 8.0),
         ],
     )
+    mocker.patch(
+        "smee.mm._fe.reweight_grads_solvent",
+        side_effect=[((torch.tensor([[9.0, 10.0]]).double(),), 11.0)],
+    )
+
     dg_0 = torch.tensor(-3.0).double()
 
     with pytest.raises(smee.mm.NotEnoughSamplesError):